neuronal subtype specification in establishing mammalian ... · areas (noctor et al., 2001; rakic,...

R

Nn

Ta

b

a

ARRAA

KNCPPLE

C

1

attbh

f0

h0b

Neuroscience Research 86 (2014) 37–49

Contents lists available at ScienceDirect

Neuroscience Research

jo ur nal homepage: www.elsev ier .com/ locate /neures

eview article

euronal subtype specification in establishing mammalianeocortical circuits

akuma Kumamotoa, Carina Hanashimaa,b,∗

Laboratory for Neocortical Development, RIKEN Center for Developmental Biology, Kobe 650-0047, JapanDepartment of Biology, Graduate School of Science, Kobe University, Kobe 657-8501, Japan

r t i c l e i n f o

rticle history:eceived 10 March 2014eceived in revised form 21 June 2014ccepted 23 June 2014vailable online 11 July 2014

a b s t r a c t

The functional integrity of the neocortical circuit relies on the precise production of diverse neuron popu-lations and their assembly during development. In recent years, extensive progress has been made in theunderstanding of the mechanisms that control differentiation of each neuronal type within the neocortex.In this review, we address how the elaborate neocortical cytoarchitecture is established from a simpleneuroepithelium based on recent studies examining the spatiotemporal mechanisms of neuronal subtype

eywords:eocortexell fate specificationalliumrojection neuron

specification. We further discuss the critical events that underlie the conversion of the stem amniotescerebrum to a mammalian-type neocortex, and extend these key findings in the light of mammalianevolution to understand how the neocortex in humans evolved from common ancestral mammals.

© 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

ayervolution

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372. The classification of neocortical glutamatergic neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383. Spatial origins of neocortical glutamatergic neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394. Temporal specification of neocortical glutamatergic subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

4.1. Cell competence and lineage of neocortical subtypes – a question revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424.2. Genetic network underlying neocortical subtype segregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

5. The mammalian-specific regulation of neocortical subtype specification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446. The evolvability of the neocortex – future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

. Introduction

The neocortex is comprised of diverse arrays of neurons thatre organized into laminar and columnar subdivisions and ishe processing center for complex behaviors, including percep-

compatible with increased size and number of functional areas dur-ing mammalian evolution (Rakic, 2009). Although its anatomicalcharacter has been long appreciated, the mechanisms underly-ing the specification and assembly of each neuronal componentof the neocortex remain largely elusive. Despite common stem

ions, voluntary movements and languages. This unique laminatedrain system is observed throughout extant monotremes toumans (Haug, 1987; Meynert, 1868) and has proved to be highly

∗ Corresponding author at: Laboratory for Neocortical Development, RIKEN Centeror Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-047, Japan. Tel.: +81 78 306 3400; fax: +81 78 306 3401.

E-mail address: [email protected] (C. Hanashima).

ttp://dx.doi.org/10.1016/j.neures.2014.07.002168-0102/© 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open accey-nc-nd/3.0/).

amniote origin, non-mammalian lineages develop highly disparatebrain cytoarchitectures, such as a single-layered cortex in rep-tiles (Dugas-Ford et al., 2012; Nomura et al., 2013) and a nuclearorganization in birds (Jarvis et al., 2013; Montiel and Molnar,2013; Nomura et al., 2008; Suzuki et al., 2012). The acquisi-
tion of the laminated brain system is, therefore, one of the keyevents that enabled unique neural processing in mammals andmay underlie high evolvability of the neocortex toward hominidevolution.
ss article under the CC BY-NC-ND license (http://creativecommons.org/licenses/

dx.doi.org/10.1016/j.neures.2014.07.002

http://www.sciencedirect.com/science/journal/01680102

http://www.elsevier.com/locate/neures

http://crossmark.crossref.org/dialog/?doi=10.1016/j.neures.2014.07.002&domain=pdf

http://creativecommons.org/licenses/by-nc-nd/3.0/

mailto:[email protected]




3 urosc

tsacusiumth

2

ipt8iwta2msvr(

bwiarsraniutithFrw2ataFbhrf

mplaosc

8 T. Kumamoto, C. Hanashima / Ne

In recent years, approaches from both developmental and evolu-ionary viewpoints have provided new insights into the molecularcenario underlying neocortical assembly and its function. Theim of this review is to decipher how the elaborate neocorticalytoarchitecture is uniquely established in mammals based on ourpdated knowledge on the mechanisms of specification of neuronalubtypes. We then examine these homologous cell componentsn non-mammalian vertebrates to address the key events thatnderlie the conversion of the cerebrum of stem amniotes to aammalian-type neocortex. Finally, we extend these findings in

he light of mammalian evolution, to address how the neocortex inumans may have evolved from ancestral mammals.

. The classification of neocortical glutamatergic neurons

Neocortical neurons can be classified into subtypes accord-ng to their connectivity, morphology, physiology and molecularroperties. Of these, two major classes based on neurotransmit-er expressions, glutamatergic projection neurons (approximately0%) and GABA (�-aminobutyric acid)-ergic interneurons (approx-

mately 20%) create the sensory representation of the physicalorld. While interneurons connect in the vicinity to provide inhibi-

ion to the local circuit, projection neurons are excitatory and sendxons to distant cortical and subcortical targets (Bartolini et al.,013; Greig et al., 2013). Although these two populations inter-ix within the mature neocortex, they are generated from different

ectors of the telencephalon. Interneurons are produced from theentral eminences (Anderson et al., 1997), whereas projection neu-ons arise locally from the progenitors of the dorsal telencephalonGorski et al., 2002).

In principle, the cytoarchitecture of the neocortex can be definedy its glutamatergic cell components. These excitatory neurons,hich are arranged into horizontal layers, undergo further mod-

fications that assemble them into tangentially organized columnsnd areas (Noctor et al., 2001; Rakic, 1988). Each column, typicallyesponding to a specific sensory stimulus, such as a body part oround representation, is considered a functional unit within theespective neocortical area. After Meynert (1868), Lewis (1878)nd Hammarberg (1895), Brodmann was the first to unify theames of neocortical subtypes according to their laminar pos-

tions and morphologies. Ever since, layers I through VI are stillsed as common terminology in identifying the glutamatergic sub-ypes organized along the radial axis from superficial to deep. It ismportant to recognize that although laminar positions are indica-ive of their neuronal identity, the advent of molecular technologyas brought forth its limitation in defining a specific subtype.or example, retrograde neuronal tracers combined with microar-ay analyses reveal further heterogeneity in cell populations evenithin the same layer (Arlotta et al., 2005; Molyneaux et al.,

009). Recent high-throughput transcriptome-profiling in rodentsnd primates has highlighted not only diverse expression pat-erns of protein-coding genes but also noncoding RNAs within andcross neocortical layers (Belgard et al., 2011; Bernard et al., 2012;ertuzinhos et al., 2014). Therefore, a given neuronal type can onlye defined by supplemental criteria, including their molecular andodological properties. Based on these, the classification of rep-esentative layer glutamatergic neurons currently falls into theollowing subtypes, which has been best delineated in mice.

Layer I is a relatively cell sparse layer, which accommodatesainly intercellular synapses of axonal fibers and dendritic tufts of

yramidal neurons. However, it consists of a unique neuron popu-ation called Cajal–Retzius (CR) cells during development. Although
pproximately 75% of CR cells present at birth die before the sec-nd postnatal week in mice (Del Rio et al., 1995; Soda et al., 2003),ome CR cells survive to adulthood (Chowdhury et al., 2010). CRells extend long horizontal axons and form synaptic contacts
ience Research 86 (2014) 37–49

with dendrites of pyramidal neurons (Marin-Padilla, 1998; Meyeret al., 1999; Soriano and Del Rio, 2005; Villar-Cervino and Marin,2012) and express Reelin, p73 (Trp73) and/or calretinin, and CXCR4,depending on their subtype of origin (De Bergeyck et al., 1998; DelRio et al., 1995; Ogawa et al., 1995; Stumm et al., 2003). CR neuronswere originally identified by their unique morphology and distri-bution within the marginal zone of developing human neocortex(reviewed by Meyer et al., 1999). These neurons control the radialmigration of projection neurons through their secretion of proteinReelin. However, recent reports also indicate their roles in prolifera-tion and areal patterning of later-born projection neurons (Griveauet al., 2010; Teissier et al., 2012).

Neurons of layers II/III have distinct features from layer IVneurons, although both are categorized into upper-layer (UL)projection neurons. Layers II/III pyramidal neurons establishinterhemispheric synaptic connections and mediate higher orderinformation processing through the integration of bilateral corti-cal information. These neurons send axons to distant ipsilateraland contralateral neocortical areas: the latter of which are calledcallosal projection neurons (CPN) and connect the two cerebralhemispheres by extending axons through the corpus callosum(Fame et al., 2011). These neurons have relatively small, pyramidal-shaped somata and confined dendritic trees, and they form axonalcollaterals with neighboring cortical regions (Gilbert and Wiesel,1979; Lund et al., 1979). During the early postnatal period, mostlayers II/III projection neurons express the transcription factorsCux1/2, Brn1/2, Satb2 and the non-transcription factors Inhba andLimch1 (Britanova et al., 2008; Franco et al., 2012; McEvilly et al.,2002; Molyneaux et al., 2009; Nieto et al., 2004). In rodents, thedistinction between layers II and III is not as clear as in primates.However, a few genes, including Frmd4b, Nnmt, Chn2 and Lpl, areexpressed in a restricted subset of layers II/III neurons during mousedevelopment (Molyneaux et al., 2009). Importantly, lineage anal-ysis using Cre recombinase expressed from the Cux2 gene locus(Cux2Cre/+ mice) has shown that Cux2-expressing cells predomi-nantly contribute to layers II–IV neurons, which defines Cux2 asan UL neuron lineage marker (Franco et al., 2012).

Neurons of layer IV, in turn, convey sensory information intothe neocortex by receiving input from peripheral organs. Theseneurons function as high-fidelity gateway for sensory inputs, main-taining strict topographic organization and information transferto a given neocortical area. The glutamatergic neurons of layerIV exhibit a variable dendritic pattern compared to other layers(Staiger et al., 2004). For example, in the somatosensory cortex,spiny stellate cells represent a distinctive class of glutamater-gic neurons. These neurons differ in their morphology from themore abundant pyramidal neurons by the lack of a polarized api-cal dendrite and confine their dendritic arbor in the same layer,while typically projecting axons to layers II/III within the column(Anderson et al., 1994; Martin and Whitteridge, 1984; Yoshimuraet al., 2005). In contrast to other layer neurons, the number of layerIV neuron specific markers is limited of which Rorb, Unc5d andKcnh5 (or Eag2) have been identified so far (Ludwig et al., 2000;Saganich et al., 1999; Schaeren-Wiemers et al., 1997; Zhong et al.,2004).

Neurons of layer V, together with layer VI neurons, are grouped asdeep-layer (DL) neurons and consist mainly of corticofugal projec-tion neurons. Layer V neurons project to the brainstem and spinalcord, and express Fezf2 and Ctip2, and a subset of these expressER81 (Chen et al., 2005a,b; Inoue et al., 2004; Molnar and Cheung,2006; Molyneaux et al., 2005; Yoneshima et al., 2006). Althoughlayer V neurons are mostly subcerebral projection neurons (SCPNs),
it is notable that approximately 20% of neocortical CPNs localize inlayer V, and these neurons are similar to layers II/III CPNs in theirmolecular expression and connectivity (Molyneaux et al., 2009).Notably, layer V contains large pyramidal neurons that are disposed

urosc

istopln2iml

ru2eaMtLmiWci1f

3

ardmbcenpmeds

tdahqFtet12wgenW2cid

T. Kumamoto, C. Hanashima / Ne

n radial clusters; these neurons express specific subsets of genesuch as Ctip2 and Id2, and are segregated from CPNs that occupyhe same layer (Kwan et al., 2012; Maruoka et al., 2011). Thesebservations imply that projection neurons of common molecularrofiles are further organized into microdomains within the same

ayer. In turn, layer VI neurons establish corticothalamic projectioneurons (CThPNs) and express Tbr1, Zfpm2, and Sox5 (Hevner et al.,001; Kwan et al., 2008). Layer VI neurons exhibit greater variabil-

ty in their dendritic patterns; however, the correspondence of theirorphology and gene expression is less defined compared to other

ayers.Subplate neurons (alternatively called layer VIb or layer VII neu-

ons), are also early-generated neurons in the neocortex that havendergone expansion during mammalian evolution (Montiel et al.,011; Smart et al., 2002). Subplate cells are identified by their deep-st position in the cortical plate and expression of CTGF, Cplx3,nd Lpar1 during the perinatal periods (Hoerder-Suabedissen andolnar, 2013); however, earlier, they share several molecular fea-

ures with layer VI neurons (Hevner et al., 2001; Kwan et al., 2008;ai et al., 2008). Subplate neurons serve as initial scaffolds for thala-ic afferents into the neocortex and provide the earliest excitatory

nputs into the neocortex (Ghosh et al., 1990; Kanold et al., 2003).hile subplate neurons are also considered to be largely transient

ells in mice (Price et al., 1997), a proportion of these cells remainn postnatal primate cortices (Judas et al., 2010; Kostovic and Rakic,980). Thus, subplate cells may also function beyond early circuitormation.

. Spatial origins of neocortical glutamatergic neurons

The intricate cytoarchitecture of the neocortex has longttracted neuroscientists to investigate how the diversity of neu-ons are created and how their precise integration is coordinateduring development. For this, it is worthwhile to consider theechanisms by which neocortical subtypes are generated along

oth the spatial and temporal axis. Despite its complexity, the neo-ortex starts as a simple sheet of neuroepithelium at the anteriornd of the neural plate of which the dorsal sector of the tele-cephalon becomes the pallium. The pallium is divided into fourroliferative zones according to molecularly definable boundaries:edial, dorsal, lateral and ventral pallium (Fig. 1A). Here, we focus

xclusively on the establishment of these subdivisions in three-imensions to address the neocortical subtypes that arise from eachector.

Extensive studies in mice have shown that early forebrain pat-erning is established between 3 and 6 somite stages (∼embryonicay (E)8.0) through the reciprocal action of transcription factorsnd morphogens. The anterior neuraxis is instructed through theead organizer activity of the anterior visceral endoderm. Subse-uently, Otx2 (induced by the anterior neuroectoderm enhancer,ig. 1A and B) establishes the forebrain and midbrain territorieshrough an antagonistic effect on Gbx2 (∼6-somite stage) (Inouet al., 2012; Kurokawa et al., 2004, 2014; Millet et al., 1999). Withinhe forebrain, the expression of Emx2 (3-somites∼) (Simeone et al.,992; Suda et al., 2001) and Pax6 (late 4-somites∼) (Inoue et al.,000) functions redundantly to establish the caudal forebrain,hich contributes to the medial and ventral pallium (shown in

reen and light blue in Fig. 1A and B) and diencephalon (Kimurat al., 2005). In parallel, rostrally, Six3 is expressed at the anterioreural plate after E8.2 (Oliver et al., 1995) (Fig. 1B) and repressesnt1 to establish the rostral forebrain domain (Lagutin et al.,

003). The expression of Fgf8 in the anterior neural ridge (ANR)ommences at approximately 4-somites (Suda et al., 1997), whichnduces Foxg1 in the Six3-expressing domain and establishes theorsal pallium and subpallium (Kobayashi et al., 2002; Lagutin

ience Research 86 (2014) 37–49 39

et al., 2003) (Fig. 1B). The boundary between the pallium and sub-pallium (pallial–subpallial boundary; PSB) is established throughcross-repression between Gli3 and Shh, and Fgf8 expression (Gutinet al., 2006; Rallu et al., 2002). Through these interactions, the bor-der between the Pax6+ pallium and the Nkx2.1+ subpallium is firstestablished around E9.5 (Shimamura et al., 1995) (Fig. 1B), whichis subsequently replaced by a Pax6/Gsx2 boundary by E12.5 (Yunet al., 2001).

After this, the entire pallium is defined by Pax6 expression inthe progenitors and Tbr1 expression in the postmitotic neurons(Puelles et al., 2000), although Tbr1 is downregulated in many of thelayers II–V neurons (Han et al., 2011). Notably, although the expres-sion of Emx2 and Pax6 extends into the dorsal pallial territory, theenhancer that drives expression in the caudal forebrain and dorsalpallium appears to be different (Kammandel et al., 1999; Kleinjanet al., 2004; Theil et al., 2002). Emx1 is further restricted in its lateralextent (Fernandez et al., 1998), where it delineates an expressionboundary between the lateral and ventral pallium (Puelles et al.,2000) (Fig. 3C, left panel). The medial pallium, in turn, is definedby the expression of multiple Wnts (Wnt3a, Wnt5a and Wnt2b)by E9.5 (Parr et al., 1993) (Fig. 1A and B). Currently, the molecularboundary that delineates the lateral and dorsal pallium progeni-tors is not clear; it is suggested that Cadherin 8 is expressed higherin the lateral pallium than that of the dorsal pallium derivatives(Medina et al., 2004).

Based on gene expression and genetic fate-mapping studies, it isclear that most neocortical glutamatergic neurons arise from pro-genitor cells of the Emx1-positive Wnt3a-negative dorsal pallialsector (Gorski et al., 2002; Louvi et al., 2007) (Fig. 3C, left). Themedial and lateral/ventral pallium, in turn, gives rise mainly to hip-pocampus and olfactory cortex/amygdala neurons (Medina et al.,2004). There are two exceptions, however, where these sectors con-tribute to neurons of the neocortex: these are the early-generatedneurons, CR cells and Dbx1-expressing transient glutamatergicneurons (Garcia-Moreno et al., 2007; Teissier et al., 2010, 2012).After a long assumption that CR cells are generated from the dorsalpallium, Meyer was the earliest to suggest that Reelin-expressingCR cells arise from a discrete pallial sector in the neuroepithe-lium and enter the neocortex by tangential migration (Meyer et al.,1999). Later, p73 was identified as an alternative CR cell markerand demonstrated a similar tangential spread from the medial andventral pallium to the dorsal pallium (Meyer et al., 2002).

The experimental evidence for non-dorsal pallium-derivedCR cells first came from exo utero electroporation of LacZ-expressing plasmids, where cells labeled in the medial palliumwith LacZ spread tangentially into the surface of the dorsal pallium(Takiguchi-Hayashi et al., 2004). Later, genetic fate-mapping usingWnt3aCre/+ mice (Yoshida et al., 2006) and Dbx1Cre/+ mice (Bielleet al., 2005) revealed the medial and ventral pallium as source ofCR cells. It is important to clarify here that (1) the medial palliumcontains the region of cortical hem and choroid plexus and (2) theventral pallium connects caudally to the thalamic eminence androstrally to the septum (Kimura et al., 2005; Puelles, 2011; Roy et al.,2013). Although these regions (cortical hem, choroid plexus, thala-mic eminence) have been considered as independent sources of CRcells (Imayoshi et al., 2008; Tissir et al., 2009; Yoshida et al., 2006),they correspond to the derivatives of the caudal forebrain, whichare initially established by Emx2 and Pax6 (Kimura et al., 2005)(Fig. 1B).

Two transcription factors, Foxg1 and Lhx2, in turn, establish thedorsal pallium progenitors. Foxg1, a forkhead-box family protein,marks the anterior forebrain from early vertebrates (Bardet et al.,
2010; Toresson et al., 1998). Consistent with its expression, Foxg1has an evolutionary conserved role in vertebrate telencephalicdevelopment; in Xenopus, zebrafish, chickens and mice, Foxg1 reg-ulates telencephalic growth (Ahlgren et al., 2003; Hanashima et al.,

40 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

Fig. 1. The genetics of early pallial patterning. (A) Spatiotemporal gene expressions in the developing forebrain before (E8.5) and after (E9.5∼) neural tube closure. Left andright hemispheres show the expression pattern of a different set of genes; same expression pattern applies to the contralateral hemisphere. Coronal view indicates spatialsubdivisions of the pallium, where dorsal pallium lies between the medial and lateral/ventral pallium. In sagittal view, the medial and lateral/ventral pallium connects atcaudal levels. DP, dorsal pallium; LP, lateral pallium; me, mesencephalon; MP, medial pallium; pr, prosencephalon; SP, subpallium; VP, ventral pallium. (B) The early forebrainpatterning in mouse embryo is established between 3 and 6 somite stages (E8.0–E8.5) through the reciprocal action of transcription factors and morphogens. Otx2 (inducedby the anterior neuroectoderm (AN) enhancer) establishes the forebrain and midbrain. Emx2 (3-somites∼) and Pax6 (4-somites∼) functions redundantly to establish thecaudal forebrain, which contributes to the medial pallium, ventral pallium and diencephalon. Six3 is expressed at the anterior neural plate around E8.2 and establish therostral forebrain domain (red). The expression of Fgf8 in the anterior neural ridge (ANR) commences at approximately 4-somites, which induces Foxg1 in the Six3-expressingdomain and establishes the dorsal pallium and subpallium. The establishment of the subpallium further requires Shh and Nkx2.1. The PSB shown as a Pax6/Nkx2.1 boundaryis later replaced with a Pax6/Gsh2 boundary by E12.5.

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 41

Fig. 2. Spatiotemporal switch in early CR cells to projection neuron identity by Foxg 1. (A) Cell-autonomous induction of Ctip2+ DL projection neurons by Foxg1. In uteroelectroporation of pCAGGS-GFP and pCAGGS-Foxg1 into E14.5 Foxg1−/− cortex examined at E18.5. (B) Temporal competence for CR cell and DL neurogenesis in wildtypeand Foxg1 mutant mice. All scheme illustrates E18.5 cortex. From left to right: (a) wildtype, (b) constitutive Foxg1 knockout (Foxg1−/−), (c) conditional removal of Foxg1expression during the DL production period (at E13), (d) late induction of Foxg1 (at E14.5) (Foxg1 E9.5–14.5 OFF, E14.5–E18.5 ON), (e) in utero electroporation of Foxg1 intoE14.5 Foxg1−/− cortex (E14.5 Foxg1 EP). Foxg1−/− results in prolonged CR cell production at the expense of DL and UL neurons. E13 conditional knockout of Foxg1 during the DLproduction period results in the reversion of DL progenitors to generate CR cells. Conversely, E14.5 induction of Foxg1 is sufficient to induce DL neurogenesis after prolongedCR neurogenesis. In utero electroporation of Foxg1 into E14.5 Foxg1−/− cortex is sufficient to induce Ctip2+ and Fezf2+ DL projection neurons, indicating cell-autonomousrequirement for Foxg1 in switching from CR cells to DL neurons (Kumamoto et al., 2013). (C) Model for the switch in neurogenesis in the cerebral cortex. Foxg1 (red) isinduced in the anterior neural ectoderm through rostral Fgf8 expression (yellow) and expands caudally in the neural plate. After neural tube closure, Foxg1 shifts the rostrallimit of caudal telencephalic gene expression (Ebf2/3, Zic3, Lhx9, Dmrt3, Eya2) within the neuroepithelium (indicated in green) and initiates projection neuron production inthe dorsal progenitors. Expression of these genes is only observed rostrally in migrating CR neurons. The cortical hem corresponds to the dorsal part of the CR cell competentregion (green) in the sagittal section. Ventrally, the caudal limits of Foxg1 expression are the PSB and thalamic eminence (Sfrp2+ and Dbx1+ region in Fig. 1A and B). cKO,conditional knockout; CPe, choroid plexus; EP, electroporation; ThE, thalamic eminence.

4 urosc

2eePielSabNpvsqeK

edlmcapMsolipd

PmeLiatolNdalmlh

FwLeattFaeelfftt


002; Regad et al., 2007) and patterning (Manuel et al., 2010; Rotht al., 2010) through antagonizing TGF-b/Smad pathways (Seoanet al., 2004) and repressing p27Kip1 expression (Hardcastle andapalopulu, 2000). Studies in mice and chickens show that Foxg1s induced by Fgf8 within the Six3-expressing domain (Kobayashit al., 2002; Shimamura et al., 1995); however, an interesting regu-atory conservation is reported in hemichordates (Pani et al., 2012).tudies in zebrafish reveal that Foxg1 establishes the dorsal palliumnd subpallium by repression of the Wnt8b promoter through itsinding to a vertebrate-conserved sequence (Danesin et al., 2009).otably, studies using conditional mutant mice identified multi-le Foxg1-repressed target genes expressed in both the medial andentral pallium (Eya2, Dmrt3, Zic3, Ebfs), and some of these bindingites were specific to mammals (Kumamoto et al., 2013). Conse-uently, in the absence of Foxg1, the medial and ventral palliumxpands at the expense of the dorsal pallium (Danesin et al., 2009;umamoto et al., 2013) (Fig. 2C).

Lhx2 is a LIM-homeodomain transcriptional factor, which isxpressed in a medial-high to lateral-low graded pattern across theorsal pallium, and it delineates the boundary with the medial pal-

ium (Monuki et al., 2001) (Fig. 3C). Both Lhx2 constitutive knockoutice and chimera studies using Lhx2−/− <-> wildtype cells indi-

ate that Lhx2 is required for dorsal pallium specification, and itsbsence results in the expansion of both the medial and ventralallium at the expense of the dorsal pallium (Bulchand et al., 2001;angale et al., 2008). Notably, the requirement for Lhx2 in the dor-

al pallium has a restricted temporal window; whereas removalf Lhx2 before E10.5 converts it to both a medial and lateral pal-ium fate, conditional knockout between E10.5 and E11.5 resultsn expansion of the lateral and ventral pallium but not the medialallium, and after E11.5, Lhx2 is no longer required to maintain theorsal pallium identity (Chou et al., 2009; Mangale et al., 2008).

Within the forebrain, the expression of Emx2 (3-somites∼) andax6 (4-somites∼) precedes that of Foxg1 and Lhx2, which com-ences around 5-somites (E8.0) and E8.5, respectively (Mangale

t al., 2008; Tao and Lai, 1992) (Fig. 1B). This implies that Foxg1 andhx2 specify the dorsal pallium after the medial and ventral palliums established (Fig. 1B). Genetic fate-mapping and loss-of-functionnalysis further imply that these two (rostral and caudal) forebrainerritories are derived from a distinct lineage; the compound lossf Emx2 and Pax6 results in the loss of the medial and ventral pal-ium but not the dorsal pallium or subpallium (Kimura et al., 2005).otably, while Foxg1 and Lhx2 are both required to establish theorsal pallium, at caudal levels, Foxg1 delineates a sharp bordert the ventral pallium and exhibits a gradient at the medial pal-ium; Lhx2 shows the opposite trend with a sharp boundary at the

edial pallium and a graded expression at the lateral/ventral pal-ium (Kumamoto et al., 2013; Monuki et al., 2001; Allen Brain Atlas,ttp://www.brain-map.org).

Currently, evidence for genetic interactions between Lhx2 andoxg1 is lacking: knockout and chimera studies have shown thatithin the cortex Foxg1−/− cells express Lhx2 caudally, whereas

hx2−/− progenitors retain Foxg1 expression laterally (Mangalet al., 2008; Muzio and Mallamaci, 2005). This implies that Foxg1nd Lhx2 function cooperatively but independently to establishhe dorsal pallium identity. This is consistent with their distinctemporal requirements for cortical specification. The removal ofoxg1 at E13 is sufficient to convert the dorsal pallium to a medialnd ventral pallium identity (Hanashima et al., 2007; Kumamotot al., 2013), but the conditional removal of Lhx2 exhibits anarly (approximately E11.5) competence window for a dorsal toateral/ventral pallium conversion (Chou et al., 2009). Another dif-
erence between Foxg1 and Lhx2 is that while Lhx2 is dispensableor subpallium development (Bulchand et al., 2001), Foxg1 is essen-ial for ventral telencephalic identity (Martynoga et al., 2005). Thus,he absence of obvious ventral pallium expansion in Foxg1−/− cells

appears to be secondary to the loss of ventral gene expression(Fig. 1A and B). These observations are consistent with the primarytargets of Foxg1 and Lhx2 being largely non-redundant (Hou et al.,2013; Kumamoto et al., 2013; Tao and Lai, 1992).

4. Temporal specification of neocortical glutamatergicsubtypes

4.1. Cell competence and lineage of neocortical subtypes – aquestion revisited

At the time each pallium domain is established, the neuro-epithelial cells of the dorsal pallium give rise to radial glial cells(RGCs), which are more fate-restricted progenitors. The successivereplacement of neuroepithelial cells to RGCs may be instructed byseveral molecules (Kang et al., 2009; Sahara and O’Leary, 2009)and terminates the competence of dorsal pallium progenitors torespond to the loss of Lhx2 (Chou et al., 2009) but still requiresFoxg1 (Hanashima et al., 2004). The earliest neurons in the neo-cortex appear at the surface of the dorsal pallium around E10–E11and are tangentially migrating CR cells generated from the medialand ventral pallium, which form the preplate. After CR cell produc-tion, most neocortical glutamatergic neurons arise from the RGCsof the dorsal pallium, which migrate radially toward the pia andposition themselves beneath the CR cells. Neurons are generatedsuccessively and migrate past the pre-existing, early-born neuronsand allocate to the more superficial layers in an “inside-out” dis-tribution, a unique pattern observed in the mammalian neocortex(Cooper, 2008; Hevner et al., 2003).

Based on both in vitro and in vivo analysis, it has been suggestedthat the sequential generation of layer subtypes is regulated by anintrinsic program that switches progenitor cell competence overtime. In vivo clonal analysis demonstrated that a common pro-genitor could contribute to neurons that encompass both deepand upper cortical layers (Luskin et al., 1988; Price and Thurlow,1988; Reid et al., 1995; Walsh and Cepko, 1988, 1992). In vitro, DLneurons were commonly generated after fewer cell divisions thanUL neurons, and progenitors from later-stage embryos were morerestricted in their ability to generate earlier-born neuronal sub-types in vitro (Shen et al., 2006) and in vivo (Frantz and McConnell,1996; McConnell, 1988; McConnell and Kaznowski, 1991). Corti-cal cells derived from mouse embryonic stem cells demonstratedthat the temporal order by which stem cells generate neocorticalglutamatergic subtypes could be replicated in vitro (Eiraku et al.,2008; Gaspard et al., 2008). These studies implied that the definedtemporal order of projection neuron subtypes in the neocortex iscontrolled by intrinsic changes in progenitor cell competence overtime.

In this regard, recently, two alternative perspectives concern-ing the lineage of neocortical neurons have been proposed. Cux2,which is expressed in layers II–IV neurons in the mature neocortex,is expressed at a low level in RGCs at early embryonic stages. Usingan inducible Cre recombinase knocked into Cux2 locus (Cux2CreER/+),a subset of RGCs was labeled by the recombination of a reporterwith tamoxifen administration at E10.5; however, these progeni-tors mainly contributed to UL neurons (Franco et al., 2012). Theseresults implied that a subpopulation of early cortical progenitorsare dedicated to produce UL neurons but are restricted in theirdifferentiation until the appropriate timing at a later corticogen-esis period. This view is somewhat different from a lineage studyusing a Fezf2 BAC-transgenic Cre mouse line, which revealed thatFezf2-expressing progenitors can mark DL–UL-glia clones during
the early corticogenesis phase and UL-glia clones at late corticogen-esis phase (Guo et al., 2013). Although a simplistic interpretation ofthese results is that neocortical progenitors comprise both lineage-restricted and progressively restricted clones, the entire picture
http://www.brain-map.org/

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 43

Fig. 3. Comparison of homologous subtypes and progenitor domains across amniotes. (A) Whole brain view of neonatal (P0) Chinese softshell turtle (Pelodiscus sinensis;reptiles), chick (Gallus gallus; birds) and mouse (Mus musculus; mammals). (B) Cross-species homology between the pallial neuron subtypes based on gene expression andconnectivity. In the turtle, the rostral cortical area D2 corresponds to input sensory zones of the anterior DVR and expresses Rorb. The layer V marker ER81 labels theintermediate and posterior fields of area D2. In birds, thalamorecipient neurons allocate to the entopallium and Field L, both of which express Rorb, a representative markerfor neocortical layer IV neurons. In turn, neocortical layer V marker ER81 is expressed in the chicken arcopallium and HA in the hyperpallium. (C) Dorsoventral patterningof the telencephalon and respective pallial domains in mouse and chick embryos. Data are from mouse (E9.5–12.5) and chick (E4–E8) expression studies of mouse: Emx1/2,Pax6, Ngn2, Dlx2, Sommer et al. (1996), Puelles et al. (2000), Yun et al. (2001), Muzio et al. (2002), Backman et al. (2005); Wnt3a, Wnt8b, Bmp4, Foxg1, Parr et al. (1993),Hanashima et al. (2007); Lhx2, Monuki et al. (2001), Chou et al. (2009), Mangale et al. (2008); Dbx1, Medina et al. (2004), Bielle et al. (2005); Sfrp2, Kim et al. (2001), andchick: Emx1/2, Lhx2, Pax6, Dlx2, von Frowein et al. (2006), Puelles et al. (2000); Foxg1, Bell et al. (2001); Ngn2, Sfrp1, von Frowein et al. (2002); Wnt8b, Garda et al., 2002.In mouse, the expression of Emx1, Emx2 and Ngn2 extends into the Wnt3a+ medial pallium domain. Emx1 is expressed in both progenitors and post-mitotic neurons in thedorsal and lateral pallium, but its expression is restricted to post-mitotic neurons in the ventral pallium. Rostrally, Foxg1 expression extends to the subpallium; at caudallevels, Foxg1 expression is absent in the ventral pallium (Kumamoto et al., 2013). While it has been suggested that Lhx2 expression is restricted to the pallium at E12.5( et al.,

v C, lateo

ortSts

4

mb

Monuki et al., 2001), at E11.5, Lhx2 expression extends into the subpallium (Chou

entricular ridge; E, entopallium; Hi, hippocampus; Hy, hyperpallium; L2, field L2; Llfactory cortex; Str, striatum, Th, thalamus.

f neocortical cell lineage and its neurogenesis timing regulationequires an unbiased and comprehensive clonal analysis to assesshe relative contribution of each lineage in the mature neocortex.uch experiments will also provide insights into the mechanismshat underlie the precise connectivity between clonally relatedister DL and UL projection neurons (Yu et al., 2009, 2012).

.2. Genetic network underlying neocortical subtype segregation

Despite the ambiguity of their lineage relationships, molecularechanisms that segregate layer neuron subtype identities have

een made clearer. Genetic studies have shown that the principal

2009). A, arcopallium; B, basorostralils; D2, field D2; DC, dorsal cortex; DVR, dorsalral cortex; M, mesopallium; MC, medial cortex; N, nidopallium; NC, neocortex; OC,

layer subtypes of the cerebral cortex are established with a closedtranscriptional network (Alcamo et al., 2008; Bedogni et al., 2010;Britanova et al., 2008; Chen et al., 2008; Han et al., 2011; McKennaet al., 2011; Srinivasan et al., 2012). Within these, repressornetworks are the major regulatory cascades responsible for seg-regating subtype identities. Tbr1, Fezf2 and Satb2 are expressed inCThPNs, SCPNs and CPNs, respectively, where the loss of any oneof these genes results in a switch to alternative subtype identities
(Alcamo et al., 2008; Chen et al., 2008; Han et al., 2011; McKennaet al., 2011). For example, in Fezf2−/− knockout mice, Satb2+ CPNsand Tbr1+ CThPNs appear at the expense of SCPNs (Bedogni et al.,2010; Chen et al., 2005a; McKenna et al., 2011; Molyneaux et al.,

4 urosc

2lnaeM(iecHeii2ceeSceml

wtrCFCtataitgcfnsjcs

5s

tdnochabiwcN

ese


005), while forced expression of Fezf2 is sufficient to reprogramayers II/III CPNs and layer IV neurons to layer V/VI corticofugaleuron identity (Chen et al., 2005b; De la Rossa et al., 2013; Rouauxnd Arlotta, 2013). In Tbr1−/− mice, DL neurons upregulate Fezf2xpression and project inappropriately to the pons (Han et al., 2011;cKenna et al., 2011). In Satb2−/− mice, Ctip2+ SCPNs increase

Britanova et al., 2008). Of these transcription factors, only Fezf2s expressed in both progenitors and post-mitotic neurons (Hiratat al., 2004), whereas others are only detectable in post-mitoticells (Alcamo et al., 2008; Arlotta et al., 2005; Britanova et al., 2008;evner et al., 2001). Furthermore, the segregation of these mark-rs is only evident in postmitotic neurons: E13.5-born DL neuronsnitially co-express Satb2 and Ctip2, but later they are segregatednto CPN and SCPN subtypes (Alcamo et al., 2008; Srinivasan et al.,012). Sox5, Fezf2 and Ctip2 are also coexpressed in many youngorticofugal neurons of layers V/VI and SP. However, as corticogen-sis proceeds, Sox5 expression in post-mitotic cells represses Fezf2xpression in layer VI neurons (Kwan et al., 2008; Lai et al., 2008;rinivasan et al., 2012). Therefore, it appears that some of theseommitments take place at postmitotic levels. However, since thexpression of many transcription factors is downregulated duringigration, the extent of cell fate decisions controlled at progenitor

evels is not clear.In this regard, Foxg1 plays a key role in early fate transition

ithin progenitors. Conditional removal of Foxg1 in DL progeni-ors switches these progenitors to adopt a CR cell fate; however, itsemoval in postmitotic neurons does not revert DL neurons intoR cells (Kumamoto et al., 2013). In turn, delayed induction ofoxg1 at E14.5 in vivo reveals that CR progenitor cells can generatetip2+/Fezf2+ DL neurons at a progressively later stage of neocor-icogenesis (Kumamoto et al., 2013) (Fig. 2A and B). Genome-widenalysis reveals that the onset of Foxg1 expression represses mul-iple transcriptional factors (Dmrt3, Eya2, Ebf2/3, and Zic3) thatre expressed in the progenitors of CR cells (Fig. 2C). These resultsndicate that although the initial medial/ventral and dorsal palliumerritories are established independently, the progenitor cells thatenerate CR neurons and DL neurons are interconvertible; theirompetence switch is strictly regulated by a single transcriptionactor, Foxg1 (Fig. 2A and B). Taken together, the specification ofeocortical layer neurons involves the following two steps: (1) theuppression of a default CR cell identity and commitment to pro-ection neuron fate through Foxg1-mediated gene cascade and (2)ross-regulatory determination of layer subtypes through subtype-pecific transcription factors (Fig. 2C).

. The mammalian-specific regulation of neocorticalubtype specification

To what extent is the developmental program that directs pat-erns of neurogenesis and their assembly ‘neocortex’ specific? Toiscuss this, it is necessary to define the homologous subtypes ofeocortical neurons and their progenitors across amniotes. Becausef the nature of evolution, such identification must rely on multipleriteria. Indeed, there is still a debate concerning the cross-speciesomology between the pallial neuron subtypes. This is because, at

glance, the cytoarchitecture of the cerebrum is highly variableetween amniotes; reptiles use a mono-layered cortex for their

nformation processing (Cheung et al., 2007; Nomura et al., 2013),hereas birds undergo nucleotypic organization to form mature

erebral circuits (Jarvis et al., 2013; Montiel and Molnar, 2013;omura et al., 2008).

Dugas-Ford et al. (2012) took particular interest in the genexpression and connectivity between neurons of the neocortex andauropsid pallium. In particular, they focused on thalamorecipi-nt neurons and SCPNs; the former corresponds to layer IV and


the latter to layer V projection neurons in mammals. In avians,visual information from the optic tectum is relayed by the nucleusrotundus of the thalamus and enters the entopallium, and auditoryinformation is relayed through the thalamic auditory nucleus toneurons in Field L (Fig. 3B). These thalamorecipient neurons expressRorb, a representative marker for neocortical layer IV neurons. Inturn, at least three of the neocortical layer V markers, Er81, Fezf2and Pcp4, are expressed in the chicken arcopallium in the aviandorsal ventricular ridge (DVR; a characteristic protrusion into thelateral ventricle in sauropsids) and hyperpallium (Fig. 3B). In theturtle, the rostral area D2 corresponds to input sensory zones ofthe anterior DVR and expresses Rorb and Eag2 (Dugas-Ford et al.,2012; Ulinski, 1986) (Fig. 3B). By contrast, the layer V marker ER81labels the intermediate and posterior fields of area D2, which areexpressed complementary with Rorb at a single cell resolution(Dugas-Ford et al., 2012) (Fig. 3B). Satb2- and Ctip2-expressing neu-rons also comprise largely complementary populations in the geckopallium (Nomura et al., 2013), although the projection targets ofthese neurons are still unclear. These observations imply that insauropsids, the homologous subtypes may allocate across multiplepallial sectors and are not solely dorsal pallium derivatives.

The correspondence of a few genes may be insufficient to claimhomology between mammals and sauropsid pallial neuron sub-types. In this regard, recently, a comprehensive transcriptomeanalysis has been performed by two groups (Belgard et al., 2013;Chen et al., 2013; Jarvis et al., 2013). Based on the expression anal-yses of 52 genes in the zebra finch, (Jarvis et al., 2013) proposeda new compartment model in avians based on gene expressionsimilarities between subdomains of the bird pallium and mam-malian neocortex. Comparative transcriptomics of over 5000 genesin the adult chick and mouse cerebrum also revealed some con-vergence between the different sectors of these species, but alsohighlighted divergent molecular characters (Belgard et al., 2013;Montiel and Molnar, 2013). Interestingly, in vitro clonal analysis inthe chick implies conservation between the temporal neurogenesisprograms of mice and chicks (Suzuki et al., 2012). In these experi-ments, chick pallial progenitors produce layer specific subtypes ina similar chronological sequence in vitro as those observed in mam-mals (Suzuki et al., 2012). Furthermore, recent birthdating studiesin the gecko showed that the Satb2- and Ctip2-expressing cells inthe dorsal pallium also exhibited a similar trend in their tempo-ral production, where many Ctip2+ cells are generated earlier thanSatb2+ cells (Nomura et al., 2013). These results raise an intrigu-ing possibility that the temporal program of the neurogenesis ofprojection neuron subtypes emerged early in stem amniotes.

Given that the gene expression, axonal connections, and eventhe temporal programs of neuronal subtypes are conserved, themechanisms that underlie the changes in the final configurationof neuronal subtype allocation within each vertebrate class appearto rely on other elements. For this, at least two changes betweenmammals and sauropsids can be argued. One possibility is that eachpallial sector may undergo disproportional expansion in saurop-sids, thereby spatially modifying their neurogenesis program. It isimportant to note that in general, the rostrocaudal and dorsoven-tral patterning of the telencephalon is conserved across amniotes,and the expression of Pax6, Tbr1, and Emx1 and the emergenceof the four pallial sectors are similar in both birds and reptilians(Puelles et al., 2000) (Fig. 3C). An exception is that the chick ven-tral pallium does not express Dbx1 as found in the mouse (Bielleet al., 2005) (Fig. 3C). Instead, the Pax6+ domain contacting thesubpallium expresses Sfrp1 (von Frowein et al., 2002), a homo-logue of Sfrp2, which is expressed in the mouse ventral pallium
(Assimacopoulos et al., 2003) (Fig. 3C). However, the subsequenttransformation of each pallial sector to mature cerebral struc-tures is quite distinct between mammals and sauropsids. Whilethe contribution of the medial pallium to the hippocampus and

urosc

pa(tl1st1rttrd

ptdbrairpb2trnS2diiRtrettmtcagdDrestc

cTastseiFeSts

neurons among different species. Hence, such mechanisms must


arahippocampal area, the lateral pallium to the olfactory cortex,nd the ventral pallium to the pallial amygdalar nuclei is similarAbellan and Medina, 2009), the avian dorsal pallium consists ofhe hyperpallium (also called the Wulst) and the ventral palliumargely contributes to the DVR (Bell et al., 2001; Striedter et al.,998). The anterior DVR contains auditory, visual, and somatosen-ory recipient regions and the neurons of the posterior DVR projectso the ventromedial and lateral hypothalamus (Bruce and Neary,995a,b). Thus, neuronal components of similar properties withespect to their input/output connections have undergone distinc-ive spatial arrangements between amniotes, which may involvehe modification of the production and migration program of neu-onal subtypes resulting in the expansion of neurons along radialimensions in mammals.

A second possibility is that mammalian-specific neuronal com-onents may impact the ultimate laminar and areal organizationhat characterizes the neocortex. A century after the originalescription by (Retzius, 1893) and (Cajal, 1899), CR cells wererought to attention by their critical roles in instructing radial neu-on migration and ‘inside-out’ six-layer neocortex formation (Ricend Curran, 2001; Tissir and Goffinet, 2003). Although the orig-nal phenotype of the spontaneous mutant mice for Reelin waseported earlier (D’Arcangelo et al., 1995; Ogawa et al., 1995), therecise mechanisms of Reelin action in neuronal migration haveeen unraveled only recently (Franco et al., 2011; Gil-Sanz et al.,013; Sekine et al., 2012, 2014). Indeed, expression studies in chick,urtle, crocodile and lizard shows that Reelin-positive, CR-like neu-ons are underrepresented in the sauropsid pallium, whereas theumber is increased in humans (Bernier et al., 1999, 2000; Cabrera-ocorro et al., 2007; Goffinet et al., 1999; Meyer, 2010; Tissir et al.,003). The correlation between an increase in the medial palliumuring evolution also suggests a concerted role in the evolutionary

ncrease of CR cells (Meyer, 2010). In lizards, the cells express-ng p73 in the dorsal pallium appears much fewer than that ofeelin-positive cells (Cabrera-Socorro et al., 2007), implying thathe regulation of these two genes in CR cells may be different ineptiles. The functional significance of CR cells is supported by anxperimental evidence in which Reelin-introduced COS7 cell wereransplanted into quail cortical slices, which prompted radial fiberso extend long processes toward the pial surface, a character for

ammalian neocortical progenitors (Nomura et al., 2008). Whilehese studies are indicative that the acquisition of CR cells was aritical event in establishing a laminated neocortex system, it islso noteworthy that reducing the number of CR cells in mice byenetic ablation (35% reduction in Wnt3aCre/+; Rosa26loxp-stop-loxp-dta

ouble heterozygous mice and 84% reduction in Wnt3aCre/+;eltaNp73Cre/+; Rosa26loxp-stop-loxp-dta triple heterozygous mice)

esults in an overall normal laminar organization at birth (Tissirt al., 2009; Yoshida et al., 2006). These results imply that theignificant increase in CR cell number and diversity during evolu-ion may serve roles beyond lamination to instruct the neocorticalytoarchitecture.

Interestingly, the binding sequences of Foxg1 to its target CRell genes are only conserved in mammals (Kumamoto et al., 2013).herefore, the regulation of CR cells by Foxg1 in itself may have been

novel acquisition of the mammalian species. Notably, the expres-ion of Foxg1 appears with a shorter delay to that of Emx2 in chickhan in mice; Foxg1 is detectable as early as Hamburger–Hamiltontage (HH) 6 in the chick anterior neural plate and is highlyxpressed at HH8, whereas Emx2 expression is low at HH8 andncreases after HH12 (Bell et al., 2001). In mouse, the onset ofoxg1 expression (5-somite stage) (Kobayashi et al., 2002; Lagutint al., 2003) follows that of Emx2 (3-somites) (Simeone et al., 1992;
uda et al., 2001) expression. The differences in their expressioniming may thus influence the early patterning of respective dor-al and medial pallial territories (Fig. 1B), thereby contributing
ience Research 86 (2014) 37–49 45

to the size expansion of the cortical hem and CR cell number inmammals.

6. The evolvability of the neocortex – future perspectives

As mentioned, CR cells may be one feature that characterizes themammalian neocortex within the amniote brains. Until recently,the identification of CR cells has relied on the expression of Reelin,which is the only marker identified to be expressed in all CR cell sub-types in mammals (even though Reelin is expressed in non-CR cells,including interneurons) (Soriano and Del Rio, 2005; Villar-Cervinoand Marin, 2012). However, the identification of multiple subtypesof CR cells with distinct molecular features naturally underscoredthe complexity of CR cells and raised a question of how and whysuch diversity of CR cells has been created. Regarding this, two non-exclusive mechanisms can explain their diversity. One is that thepresence of specific morphogens in each pallial sector may intro-duce a regional character to the CR cell subtypes. For example, themedial pallium is the source of Wnts and Bmps, and the ventral pal-lium expresses Sfrp2 caudally and Fgf8, 17, and 18 rostrally. Thesemay induce differential gene expressions in regional CR cells. Thesecond explanation is that CR cells may represent a default state ofcortical progenitors; therefore, these neurons retain a wider molec-ular repertoire due to the higher number of accessible chromatin atthe earliest competent state. Progression of the corticogenesis pro-gram may restrict the configuration of the chromatin and limit thenumber of genes expressed in subsequent-born projection neurons.

Are multiple origins and subtypes of CR cells a consequence ora cause of sauropsid-to-mammalian brain conversion? It is possi-ble, that the neocortical evolution may itself require the increase inboth the number of CR cells and their molecular diversity. Pollardet al. (2006) scanned ancestrally conserved genomic regions tosearch for regions that showed significant acceleration of substitut-ions in the human lineage, and found that many of these humanaccelerated regions (HARs) are associated with genes involved intranscriptional regulation and neural development. In particular,a 118 bp HAR1 region showed the most accelerated change and isexpressed specifically in CR cells in human embryonic neocortex(Pollard et al., 2006). This suggests that molecular heterogeneityof CR cells may be associated with new functions during neocor-tical evolution. Consistent with this view, the manipulation in thenumber and distribution of CR cells can modify progenitor prop-erties in a region-specific manner, implying that CR cell subtypesmay serve as mediators of early neocortical patterning (Griveauet al., 2010). As opposed to the projection neurons that have dis-cerned functions in the neocortical circuit formation, the extentof heterogeneity and functional repertoire of early-born neuronsis still largely unknown, partly because the molecular diversity ofthese subtypes has only been appreciated recently (Griveau et al.,2010; Hoerder-Suabedissen and Molnar, 2013; Kumamoto et al.,2013). Further investigations into the molecular functions of CRcells will provide insights into the ontogeny and elaboration of amammalian-specific neocortical circuit formation.

Currently, the mechanisms of mammalian neocortical subtypespecification stand on the premise that the molecules and theiractivity identified in mice are generally conserved among mam-mals. However, the size of the neocortex differs substantially indifferent species ranging from soricomorpha to cetaceans (Cataniaet al., 1999; Naumann et al., 2012). Taking this into consider-ation, the regulation of the production of neocortical subtypesrequires a developmental process in the broader context of evolu-tion that ultimately balances the numbers of functionally distinct

utilize a system adaptable to changes in cortical size during mam-malian evolution. For example, Foxg1 target transcription factorsexhibit a caudal-to-rostral gradient expression within the pallium,

4 urosc

iFcsTttn

Hneeaeeraptti(

7

stuuahtiac2Wtaitsiqeco

A

vsit“J

R

A

A


mplying that the onset of Foxg1 expression induced by anteriorGF8 (Shimamura and Rubenstein, 1997) might repress early cellompetence in an opposed rostral-to-caudal gradient, resulting in apatiotemporal switch from CR cell to DL neuron identity (Fig. 2C).herefore, the expansion of mammalian cortical size during evolu-ion may have incorporated efficient, compensatory mechanismso generate sufficient numbers of CR cells prior to the onset of DLeurogenesis, which requires CR cells for their radial migration.

How is the neuronal number of other layer subtypes controlled?igher-order mammals, such as primates, have large gyrencephaliceocortex. Recent studies have shown that the disproportionatexpansion of neocortical surface area and neuron number duringvolution relies on the acquisition of novel progenitor types anddditional germinal zones including outer RGCs and SVZ (Betizeaut al., 2013; Fietz et al., 2010; Geschwind and Rakic, 2013; Hansent al., 2010; Lui et al., 2011; Shitamukai et al., 2011). Therefore, theegulation of a switch from DL to UL neurogenesis will also require

system that is adaptable to increases in cortical size, gestationaleriod, cell cycle, and division modes during mammalian evolu-ion (Fietz and Huttner, 2011; Lui et al., 2011). The mechanismshat balance the production of UL to DL neurogenesis await furthernvestigation, including the segregation timing of their lineagesFranco et al., 2012; Guo et al., 2013).

. Conclusions

The neocortical structure is specialized for processing an exten-ive range of information and complex behaviors that are uniqueo mammalian vertebrates. At molecular levels, the mechanismsnderlying the specification of neuronal subtypes have begun tonravel; however, that much remains to be explored about whennd how these fate commitments takes place. Although this reviewighlights the significance of neocortical assembly in mammals,hese insights also imply that neuronal specification and pattern-ng may involve species-specific regulatory mechanisms in reptilesnd birds. Of course, one cannot argue the presence of higherognitive processing in birds and reptiles (Reiner and Northcutt,000) despite the lack of distinctive laminated cytoarchitecture.hile an anatomically remote structure such as the DVR makes

he direct comparison of neuronal subtypes between mammalsnd sauropsid brains devious, combinatorial approaches includ-ng molecular function and lineage analysis will eventually connectheir ontogeny. Detailed understanding of the roles of mammalian-pecific neuron population such as CR cells will likely provide newnsights into neocortical development. Taking into account all theseuestions, future experiments addressing how the neocortex isstablished from an ancestral dorsal telencephalon will place theritical piece of the puzzle concerning the functional significancef the human neocortical circuit.

cknowledgements

We thank T. Hirasawa and S. Kuratani (RIKEN CDB) for pro-iding us with the neonate Chinese soft-shelled turtles (Pelodiscusinensis). We thank all members of the Hanashima laboratory fornsightful comments and discussions. This study was supportedhrough a Grant-in-Aid for Scientific Research on Innovative AreasNeural Diversity and Neocortical Organization” from the MEXT ofapan (25123725) to C.H.

eferences

bellan, A., Medina, L., 2009. Subdivisions and derivatives of the chicken subpalliumbased on expression of LIM and other regulatory genes and markers of neuronsubpopulations during development. J. Comp. Neurol. 515, 465–501.

hlgren, S., Vogt, P., Bronner-Fraser, M., 2003. Excess FoxG1 causes overgrowth ofthe neural tube. J. Neurobiol. 57, 337–349.


Alcamo, E.A., Chirivella, L., Dautzenberg, M., Dobreva, G., Farinas, I., Grosschedl, R.,McConnell, S.K., 2008. Satb2 regulates callosal projection neuron identity in thedeveloping cerebral cortex. Neuron 57, 364–377.

Anderson, J.C., Douglas, R.J., Martin, K.A., Nelson, J.C., 1994. Synaptic output of phys-iologically identified spiny stellate neurons in cat visual cortex. J. Comp. Neurol.341, 16–24.

Anderson, S.A., Eisenstat, D.D., Shi, L., Rubenstein, J.L., 1997. Interneuron migra-tion from basal forebrain to neocortex: dependence on Dlx genes. Science 278,474–476.

Arlotta, P., Molyneaux, B.J., Chen, J., Inoue, J., Kominami, R., Macklis, J.D., 2005.Neuronal subtype-specific genes that control corticospinal motor neuron devel-opment in vivo. Neuron 45, 207–221.

Assimacopoulos, S., Grove, E.A., Ragsdale, C.W., 2003. Identification of a Pax6-dependent epidermal growth factor family signaling source at the lateral edgeof the embryonic cerebral cortex. J. Neurosci. 23, 6399–6403.

Backman, M., Machon, O., Mygland, L., van den Bout, C.J., Zhong, W., Taketo, M.M.,Krauss, S., 2005. Effects of canonical Wnt signaling on dorso-ventral specificationof the mouse telencephalon. Dev. Biol. 279, 155–168.

Bardet, S.M., Ferran, J.L., Sanchez-Arrones, L., Puelles, L., 2010. Ontogenetic expres-sion of sonic hedgehog in the chicken subpallium. Front. Neuroanat. 4, 28,http://dx.doi.org/10.3389/fnana.2010.00028.

Bartolini, G., Ciceri, G., Marin, O., 2013. Integration of GABAergic interneurons intocortical cell assemblies: lessons from embryos and adults. Neuron 79, 849–864.

Bedogni, F., Hodge, R.D., Elsen, G.E., Nelson, B.R., Daza, R.A., Beyer, R.P., Bammler, T.K.,Rubenstein, J.L., Hevner, R.F., 2010. Tbr1 regulates regional and laminar identityof postmitotic neurons in developing neocortex. Proc. Natl. Acad. Sci. U.S.A. 107,13129–13134.

Belgard, T.G., Marques, A.C., Oliver, P.L., Abaan, H.O., Sirey, T.M., Hoerder-Suabedissen, A., Garcia-Moreno, F., Molnar, Z., Margulies, E.H., Ponting, C.P.,2011. A transcriptomic atlas of mouse neocortical layers. Neuron 71, 605–616.

Belgard, T.G., Montiel, J.F., Wang, W.Z., Garcia-Moreno, F., Margulies, E.H., Ponting,C.P., Molnar, Z., 2013. Adult pallium transcriptomes surprise in not reflectingpredicted homologies across diverse chicken and mouse pallial sectors. Proc.Natl. Acad. Sci. U.S.A. 110, 13150–13155.

Bell, E., Ensini, M., Gulisano, M., Lumsden, A., 2001. Dynamic domains of gene expres-sion in the early avian forebrain. Dev. Biol. 236, 76–88.

Bernard, A., Lubbers, L.S., Tanis, K.Q., Luo, R., Podtelezhnikov, A.A., Finney, E.M.,McWhorter, M.M., Serikawa, K., Lemon, T., Morgan, R., Copeland, C., Smith, K.,Cullen, V., Davis-Turak, J., Lee, C.K., Sunkin, S.M., Loboda, A.P., Levine, D.M., Stone,D.J., Hawrylycz, M.J., Roberts, C.J., Jones, A.R., Geschwind, D.H., Lein, E.S., 2012.Transcriptional architecture of the primate neocortex. Neuron 73, 1083–1099.

Bernier, B., Bar, I., D’Arcangelo, G., Curran, T., Goffinet, A.M., 2000. Reelin mRNAexpression during embryonic brain development in the chick. J. Comp. Neurol.422, 448–463.

Bernier, B., Bar, I., Pieau, C., Lambert De Rouvroit, C., Goffinet, A.M., 1999. ReelinmRNA expression during embryonic brain development in the turtle Emys orbic-ularis. J. Comp. Neurol. 413, 463–479.

Betizeau, M., Cortay, V., Patti, D., Pfister, S., Gautier, E., Bellemin-Menard, A., Afanassi-eff, M., Huissoud, C., Douglas, R.J., Kennedy, H., Dehay, C., 2013. Precursordiversity and complexity of lineage relationships in the outer subventricularzone of the primate. Neuron 80, 442–457.

Bielle, F., Griveau, A., Narboux-Neme, N., Vigneau, S., Sigrist, M., Arber, S., Wassef,M., Pierani, A., 2005. Multiple origins of Cajal–Retzius cells at the borders of thedeveloping pallium. Nat. Neurosci. 8, 1002–1012.

Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K.Y., Schwark, M., Gyorgy, A.,Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., Sestan, N., Molnar, Z., Tarabykin,V., 2008. Satb2 is a postmitotic determinant for upper-layer neuron specificationin the neocortex. Neuron 57, 378–392.

Bruce, L.L., Neary, T.J., 1995a. Afferent projections to the lateral and dorsomedialhypothalamus in a lizard, Gekko gecko. Brain Behav. Evol. 46, 30–42.

Bruce, L.L., Neary, T.J., 1995b. Afferent projections to the ventromedial hypothalamicnucleus in a lizard, Gekko gecko. Brain Behav. Evol. 46, 14–29.

Bulchand, S., Grove, E.A., Porter, F.D., Tole, S., 2001. LIM-homeodomain gene Lhx2regulates the formation of the cortical hem. Mech. Dev. 100, 165–175.

Cabrera-Socorro, A., Hernandez-Acosta, N.C., Gonzalez-Gomez, M., Meyer, G., 2007.Comparative aspects of p73 and Reelin expression in Cajal–Retzius cells and thecortical hem in lizard, mouse and human. Brain Res. 1132, 59–70.

Cajal, S.R., 1899. Estudios sobre la corteza cerebral humana. Oxford University Press,Oxford.

Catania, K.C., Lyon, D.C., Mock, O.B., Kaas, J.H., 1999. Cortical organization in shrews:evidence from five species. J. Comp. Neurol. 410, 55–72.

Chen, B., Schaevitz, L.R., McConnell, S.K., 2005a. Fezl regulates the differentiationand axon targeting of layer 5 subcortical projection neurons in cerebral cortex.Proc. Natl. Acad. Sci. U.S.A. 102, 17184–17189.

Chen, B., Wang, S.S., Hattox, A.M., Rayburn, H., Nelson, S.B., McConnell, S.K., 2008.The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projec-tion neurons in the developing cerebral cortex. Proc. Natl. Acad. Sci. U.S.A. 105,11382–11387.

Chen, C.C., Winkler, C.M., Pfenning, A.R., Jarvis, E.D., 2013. Molecular profiling of thedeveloping avian telencephalon: regional timing and brain subdivision conti-nuities. J. Comp. Neurol. 521, 3666–3701.

Chen, J.G., Rasin, M.R., Kwan, K.Y., Sestan, N., 2005b. Zfp312 is required for subcorticalaxonal projections and dendritic morphology of deep-layer pyramidal neuronsof the cerebral cortex. Proc. Natl. Acad. Sci. U.S.A. 102, 17792–17797.

Cheung, A.F., Pollen, A.A., Tavare, A., DeProto, J., Molnar, Z., 2007. Comparativeaspects of cortical neurogenesis in vertebrates. J. Anat. 211, 164–176.

http://refhub.elsevier.com/S0168-0102(14)00124-2/sbref0005






























































































































































dx.doi.org/10.3389/fnana.2010.00028






































































































































































































































































































































































































































urosc

C

C

C

D

D

D

D

D

D

E

F

F

F

F

F

F

F

F

G

G

G

G

G

G

G

G

G

G

G

G


hou, S.J., Perez-Garcia, C.G., Kroll, T.T., O’Leary, D.D., 2009. Lhx2 specifies regionalfate in Emx1 lineage of telencephalic progenitors generating cerebral cortex.Nat. Neurosci. 12, 1381–1389.

howdhury, T.G., Jimenez, J.C., Bomar, J.M., Cruz-Martin, A., Cantle, J.P., Portera-Cailliau, C., 2010. Fate of Cajal–Retzius neurons in the postnatal mouseneocortex. Front. Neuroanat. 4, 10.

ooper, J.A., 2008. A mechanism for inside-out lamination in the neocortex. TrendsNeurosci. 31, 113–119.

’Arcangelo, G., Miao, G.G., Chen, S.C., Soares, H.D., Morgan, J.I., Curran, T., 1995. Aprotein related to extracellular matrix proteins deleted in the mouse mutantreeler. Nature 374, 719–723.

anesin, C., Peres, J.N., Johansson, M., Snowden, V., Cording, A., Papalopulu, N.,Houart, C., 2009. Integration of telencephalic Wnt and hedgehog signaling centeractivities by Foxg1. Dev. Cell 16, 576–587.

e Bergeyck, V., Naerhuyzen, B., Goffinet, A.M., Lambert de Rouvroit, C., 1998. Apanel of monoclonal antibodies against reelin, the extracellular matrix proteindefective in reeler mutant mice. J. Neurosci. Methods 82, 17–24.

e la Rossa, A., Bellone, C., Golding, B., Vitali, I., Moss, J., Toni, N., Luscher, C., Jabaudon,D., 2013. In vivo reprogramming of circuit connectivity in postmitotic neocorti-cal neurons. Nat. Neurosci. 16, 193–200.

el Rio, J.A., Martinez, A., Fonseca, M., Auladell, C., Soriano, E., 1995. Glutamate-like immunoreactivity and fate of Cajal–Retzius cells in the murine cortex asidentified with calretinin antibody. Cereb. Cortex 5, 13–21.

ugas-Ford, J., Rowell, J.J., Ragsdale, C.W., 2012. Cell-type homologies and the originsof the neocortex. Proc. Natl. Acad. Sci. U.S.A. 109, 16974–16979.

iraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Mat-sumura, M., Wataya, T., Nishiyama, A., Muguruma, K., Sasai, Y., 2008.Self-organized formation of polarized cortical tissues from ESCs and its activemanipulation by extrinsic signals. Cell Stem Cell 3, 519–532.

ame, R.M., MacDonald, J.L., Macklis, J.D., 2011. Development, specification, anddiversity of callosal projection neurons. Trends Neurosci. 34, 41–50.

ernandez, A.S., Pieau, C., Reperant, J., Boncinelli, E., Wassef, M., 1998. Expression ofthe Emx-1 and Dlx-1 homeobox genes define three molecularly distinct domainsin the telencephalon of mouse, chick, turtle and frog embryos: implicationsfor the evolution of telencephalic subdivisions in amniotes. Development 125,2099–2111.

ertuzinhos, S., Li, M., Kawasawa, Y.I., Ivic, V., Franjic, D., Singh, D., Crair, M., Sestan,N., 2014. Laminar and temporal expression dynamics of coding and noncodingRNAs in the mouse neocortex. Cell Rep. 6, 938–950.

ietz, S.A., Huttner, W.B., 2011. Cortical progenitor expansion, self-renewal and neu-rogenesis – a polarized perspective. Curr. Opin. Neurobiol. 21, 23–35.

ietz, S.A., Kelava, I., Vogt, J., Wilsch-Brauninger, M., Stenzel, D., Fish, J.L., Corbeil, D.,Riehn, A., Distler, W., Nitsch, R., Huttner, W.B., 2010. OSVZ progenitors of humanand ferret neocortex are epithelial-like and expand by integrin signaling. Nat.Neurosci. 13, 690–699.

ranco, S.J., Gil-Sanz, C., Martinez-Garay, I., Espinosa, A., Harkins-Perry, S.R., Ramos,C., Muller, U., 2012. Fate-restricted neural progenitors in the mammalian cere-bral cortex. Science 337, 746–749.

ranco, S.J., Martinez-Garay, I., Gil-Sanz, C., Harkins-Perry, S.R., Muller, U., 2011.Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migrationand lamination in the neocortex. Neuron 69, 482–497.

rantz, G.D., McConnell, S.K., 1996. Restriction of late cerebral cortical progenitorsto an upper-layer fate. Neuron 17, 55–61.

arcia-Moreno, F., Lopez-Mascaraque, L., De Carlos, J.A., 2007. Origins and migratoryroutes of murine Cajal–Retzius cells. J. Comp. Neurol. 500, 419–432.

arda, A.L., Puelles, L., Rubenstein, J.L., Medina, L., 2002. Expression patterns ofWnt8b and Wnt7b in the chicken embryonic brain suggest a correlation withforebrain patterning centers and morphogenesis. Neuroscience 113, 689–698.

aspard, N., Bouschet, T., Hourez, R., Dimidschstein, J., Naeije, G., van den Ameele, J.,Espuny-Camacho, I., Herpoel, A., Passante, L., Schiffmann, S.N., Gaillard, A., Van-derhaeghen, P., 2008. An intrinsic mechanism of corticogenesis from embryonicstem cells. Nature 455, 351–357.

eschwind, D.H., Rakic, P., 2013. Cortical evolution: judge the brain by its cover.Neuron 80, 633–647.

hosh, A., Antonini, A., McConnell, S.K., Shatz, C.J., 1990. Requirement for subplateneurons in the formation of thalamocortical connections. Nature 347, 179–181.

il-Sanz, C., Franco, S.J., Martinez-Garay, I., Espinosa, A., Harkins-Perry, S., Muller, U.,2013. Cajal–Retzius cells instruct neuronal migration by coincidence signalingbetween secreted and contact-dependent guidance cues. Neuron 79, 461–477.

ilbert, C.D., Wiesel, T.N., 1979. Morphology and intracortical projections of func-tionally characterised neurones in the cat visual cortex. Nature 280, 120–125.

offinet, A.M., Bar, I., Bernier, B., Trujillo, C., Raynaud, A., Meyer, G., 1999. Reelinexpression during embryonic brain development in lacertilian lizards. J. Comp.Neurol. 414, 533–550.

orski, J.A., Talley, T., Qiu, M., Puelles, L., Rubenstein, J.L., Jones, K.R., 2002. Corticalexcitatory neurons and glia, but not GABAergic neurons, are produced in theEmx1-expressing lineage. J. Neurosci. 22, 6309–6314.

reig, L.C., Woodworth, M.B., Galazo, M.J., Padmanabhan, H., Macklis, J.D., 2013.Molecular logic of neocortical projection neuron specification, development anddiversity. Nat. Rev. Neurosci. 14, 755–769.

riveau, A., Borello, U., Causeret, F., Tissir, F., Boggetto, N., Karaz, S., Pierani, A., 2010.
A novel role for Dbx1-derived Cajal–Retzius cells in early regionalization of thecerebral cortical neuroepithelium. PLoS Biol. 8, e1000440.
uo, C., Eckler, M.J., McKenna, W.L., McKinsey, G.L., Rubenstein, J.L., Chen, B., 2013.Fezf2 expression identifies a multipotent progenitor for neocortical projectionneurons, astrocytes, and oligodendrocytes. Neuron 80, 1167–1174.

ience Research 86 (2014) 37–49 47

Gutin, G., Fernandes, M., Palazzolo, L., Paek, H., Yu, K., Ornitz, D.M., McConnell, S.K.,Hebert, J.M., 2006. FGF signalling generates ventral telencephalic cells indepen-dently of SHH. Development 133, 2937–2946.

Hammarberg, C., 1895. Studien über Klinik und Pathologie der Idiotie nebst Unter-suchungen über die normale Anatomie der Hirnrinde. Upsala, Berlin.

Han, W., Kwan, K.Y., Shim, S., Lam, M.M., Shin, Y., Xu, X., Zhu, Y., Li, M., Sestan, N., 2011.TBR1 directly represses Fezf2 to control the laminar origin and development ofthe corticospinal tract. Proc. Natl. Acad. Sci. U.S.A. 108, 3041–3046.

Hanashima, C., Fernandes, M., Hebert, J.M., Fishell, G., 2007. The role of Foxg1 anddorsal midline signaling in the generation of Cajal–Retzius subtypes. J. Neurosci.27, 11103–11111.

Hanashima, C., Li, S.C., Shen, L., Lai, E., Fishell, G., 2004. Foxg1 suppresses early corticalcell fate. Science 303, 56–59.

Hanashima, C., Shen, L., Li, S.C., Lai, E., 2002. Brain factor-1 controls the prolifer-ation and differentiation of neocortical progenitor cells through independentmechanisms. J. Neurosci. 22, 6526–6536.

Hansen, D.V., Lui, J.H., Parker, P.R., Kriegstein, A.R., 2010. Neurogenic radial glia inthe outer subventricular zone of human neocortex. Nature 464, 554–561.

Hardcastle, Z., Papalopulu, N., 2000. Distinct effects of XBF-1 in regulating thecell cycle inhibitor p27(XIC1) and imparting a neural fate. Development 127,1303–1314.

Haug, H., 1987. Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: astereological investigation of man and his variability and a comparison withsome mammals (primates, whales, marsupials, insectivores, and one elephant).Am. J. Anat. 180, 126–142.

Hevner, R.F., Daza, R.A., Rubenstein, J.L., Stunnenberg, H., Olavarria, J.F., Englund, C.,2003. Beyond laminar fate: toward a molecular classification of cortical projec-tion/pyramidal neurons. Dev. Neurosci. 25, 139–151.

Hevner, R.F., Shi, L., Justice, N., Hsueh, Y., Sheng, M., Smiga, S., Bulfone, A., Goffinet,A.M., Campagnoni, A.T., Rubenstein, J.L., 2001. Tbr1 regulates differentiation ofthe preplate and layer 6. Neuron 29, 353–366.

Hirata, T., Suda, Y., Nakao, K., Narimatsu, M., Hirano, T., Hibi, M., 2004. Zinc fingergene fez-like functions in the formation of subplate neurons and thalamocorticalaxons. Dev. Dyn. 230, 546–556.

Hoerder-Suabedissen, A., Molnar, Z., 2013. Molecular diversity of early-born sub-plate neurons. Cereb. Cortex 23, 1473–1483.

Hou, P.S., Chuang, C.Y., Kao, C.F., Chou, S.J., Stone, L., Ho, H.N., Chien, C.L., Kuo,H.C., 2013. LHX2 regulates the neural differentiation of human embryonic stemcells via transcriptional modulation of PAX6 and CER1. Nucleic Acids Res. 41,7753–7770.

Imayoshi, I., Shimogori, T., Ohtsuka, T., Kageyama, R., 2008. Hes genes and neu-rogenin regulate non-neural versus neural fate specification in the dorsaltelencephalic midline. Development 135, 2531–2541.

Inoue, F., Kurokawa, D., Takahashi, M., Aizawa, S., 2012. Gbx2 directly restricts Otx2expression to forebrain and midbrain, competing with class III POU factors. Mol.Cell. Biol. 32, 2618–2627.

Inoue, K., Terashima, T., Nishikawa, T., Takumi, T., 2004. Fez1 is layer-specificallyexpressed in the adult mouse neocortex. Eur. J. Neurosci. 20, 2909–2916.

Inoue, T., Nakamura, S., Osumi, N., 2000. Fate mapping of the mouse prosencephalicneural plate. Dev. Biol. 219, 373–383.

Jarvis, E.D., Yu, J., Rivas, M.V., Horita, H., Feenders, G., Whitney, O., Jarvis, S.C., Jarvis,E.R., Kubikova, L., Puck, A.E., Siang-Bakshi, C., Martin, S., McElroy, M., Hara, E.,Howard, J., Pfenning, A., Mouritsen, H., Chen, C.C., Wada, K., 2013. Global viewof the functional molecular organization of the avian cerebrum: mirror imagesand functional columns. J. Comp. Neurol. 521, 3614–3665.

Judas, M., Sedmak, G., Pletikos, M., Jovanov-Milosevic, N., 2010. Populations of sub-plate and interstitial neurons in fetal and adult human telencephalon. J. Anat.217, 381–399.

Kammandel, B., Chowdhury, K., Stoykova, A., Aparicio, S., Brenner, S., Gruss, P., 1999.Distinct cis-essential modules direct the time-space pattern of the Pax6 geneactivity. Dev. Biol. 205, 79–97.

Kang, W., Wong, L.C., Shi, S.H., Hebert, J.M., 2009. The transition from radial glial tointermediate progenitor cell is inhibited by FGF signaling during corticogenesis.J. Neurosci. 29, 14571–14580.

Kanold, P.O., Kara, P., Reid, R.C., Shatz, C.J., 2003. Role of subplate neurons in func-tional maturation of visual cortical columns. Science 301, 521–525.

Kim, A.S., Anderson, S.A., Rubenstein, J.L., Lowenstein, D.H., Pleasure, S.J., 2001. Pax-6regulates expression of SFRP-2 and Wnt-7b in the developing CNS. J. Neurosci.21, RC132.

Kimura, J., Suda, Y., Kurokawa, D., Hossain, Z.M., Nakamura, M., Takahashi, M., Hara,A., Aizawa, S., 2005. Emx2 and Pax6 function in cooperation with Otx2 and Otx1to develop caudal forebrain primordium that includes future archipallium. J.Neurosci. 25, 5097–5108.

Kleinjan, D.A., Seawright, A., Childs, A.J., van Heyningen, V., 2004. Conservedelements in Pax6 intron 7 involved in (auto)regulation and alternative tran-scription. Dev. Biol. 265, 462–477.

Kobayashi, D., Kobayashi, M., Matsumoto, K., Ogura, T., Nakafuku, M., Shimamura,K., 2002. Early subdivisions in the neural plate define distinct competence forinductive signals. Development 129, 83–93.

Kostovic, I., Rakic, P., 1980. Cytology and time of origin of interstitial neurons in thewhite matter in infant and adult human and monkey telencephalon. J. Neuro-
cytol. 9, 219–242.
Kumamoto, T., Toma, K., Gunadi McKenna, W.L., Kasukawa, T., Katzman, S., Chen,B., Hanashima, C., 2013. Foxg1 coordinates the switch from nonradially to radi-ally migrating glutamatergic subtypes in the neocortex through spatiotemporalrepression. Cell Rep. 3, 931–945.

















































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































4 urosc

K

K

K

K

L

L

LL

L

L

L

L

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

Development 137, 1553–1562.


urokawa, D., Ohmura, T., Sakurai, Y., Inoue, K., Suda, Y., Aizawa, S., 2014. Otx2expression in anterior neuroectoderm and forebrain/midbrain is directed bymore than six enhancers. Dev. Biol. 387, 203–213.

urokawa, D., Takasaki, N., Kiyonari, H., Nakayama, R., Kimura-Yoshida, C., Matsuo,I., Aizawa, S., 2004. Regulation of Otx2 expression and its functions in mouseepiblast and anterior neuroectoderm. Development 131, 3307–3317.

wan, K.Y., Lam, M.M., Johnson, M.B., Dube, U., Shim, S., Rasin, M.R., Sousa, A.M., Fer-tuzinhos, S., Chen, J.G., Arellano, J.I., Chan, D.W., Pletikos, M., Vasung, L., Rowitch,D.H., Huang, E.J., Schwartz, M.L., Willemsen, R., Oostra, B.A., Rakic, P., Heffer, M.,Kostovic, I., Judas, M., Sestan, N., 2012. Species-dependent posttranscriptionalregulation of NOS1 by FMRP in the developing cerebral cortex. Cell 149, 899–911.

wan, K.Y., Lam, M.M., Krsnik, Z., Kawasawa, Y.I., Lefebvre, V., Sestan, N., 2008. SOX5postmitotically regulates migration, postmigratory differentiation, and projec-tions of subplate and deep-layer neocortical neurons. Proc. Natl. Acad. Sci. U.S.A.105, 16021–16026.

agutin, O.V., Zhu, C.C., Kobayashi, D., Topczewski, J., Shimamura, K., Puelles, L., Rus-sell, H.R., McKinnon, P.J., Solnica-Krezel, L., Oliver, G., 2003. Six3 repression ofWnt signaling in the anterior neuroectoderm is essential for vertebrate forebraindevelopment. Genes Dev. 17, 368–379.

ai, T., Jabaudon, D., Molyneaux, B.J., Azim, E., Arlotta, P., Menezes, J.R., Macklis, J.D.,2008. SOX5 controls the sequential generation of distinct corticofugal neuronsubtypes. Neuron 57, 232–247.

ewis, B., 1878. On the comparative structure of the cortex cerebri. Brain 1, 79–96.ouvi, A., Yoshida, M., Grove, E.A., 2007. The derivatives of the Wnt3a lineage in the

central nervous system. J. Comp. Neurol. 504, 550–569.udwig, J., Weseloh, R., Karschin, C., Liu, Q., Netzer, R., Engeland, B., Stansfeld, C.,

Pongs, O., 2000. Cloning and functional expression of rat eag2, a new mem-ber of the ether-a-go-go family of potassium channels and comparison of itsdistribution with that of eag1. Mol. Cell. Neurosci. 16, 59–70.

ui, J.H., Hansen, D.V., Kriegstein, A.R., 2011. Development and evolution of thehuman neocortex. Cell 146, 18–36.

und, J.S., Henry, G.H., MacQueen, C.L., Harvey, A.R., 1979. Anatomical organizationof the primary visual cortex (area 17) of the cat. A comparison with area 17 ofthe macaque monkey. J. Comp. Neurol. 184, 599–618.

uskin, M.B., Pearlman, A.L., Sanes, J.R., 1988. Cell lineage in the cerebral cortex ofthe mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron 1,635–647.

angale, V.S., Hirokawa, K.E., Satyaki, P.R., Gokulchandran, N., Chikbire, S., Subra-manian, L., Shetty, A.S., Martynoga, B., Paul, J., Mai, M.V., Li, Y., Flanagan, L.A.,Tole, S., Monuki, E.S., 2008. Lhx2 selector activity specifies cortical identity andsuppresses hippocampal organizer fate. Science 319, 304–309.

anuel, M., Martynoga, B., Yu, T., West, J.D., Mason, J.O., Price, D.J., 2010. The tran-scription factor Foxg1 regulates the competence of telencephalic cells to adoptsubpallial fates in mice. Development 137, 487–497.

arin-Padilla, M., 1998. Cajal–Retzius cells and the development of the neocortex.Trends Neurosci. 21, 64–71.

artin, K.A., Whitteridge, D., 1984. Form, function and intracortical projections ofspiny neurones in the striate visual cortex of the cat. J. Physiol. 353, 463–504.

artynoga, B., Morrison, H., Price, D.J., Mason, J.O., 2005. Foxg1 is required forspecification of ventral telencephalon and region-specific regulation of dorsaltelencephalic precursor proliferation and apoptosis. Dev. Biol. 283, 113–127.

aruoka, H., Kubota, K., Kurokawa, R., Tsuruno, S., Hosoya, T., 2011. Periodic organi-zation of a major subtype of pyramidal neurons in neocortical layer V. J. Neurosci.31, 18522–18542.

cConnell, S.K., 1988. Fates of visual cortical neurons in the ferret after isochronicand heterochronic transplantation. J. Neurosci. 8, 945–974.

cConnell, S.K., Kaznowski, C.E., 1991. Cell cycle dependence of laminar determi-nation in developing neocortex. Science 254, 282–285.

cEvilly, R.J., de Diaz, M.O., Schonemann, M.D., Hooshmand, F., Rosenfeld, M.G.,2002. Transcriptional regulation of cortical neuron migration by POU domainfactors. Science 295, 1528–1532.

cKenna, W.L., Betancourt, J., Larkin, K.A., Abrams, B., Guo, C., Rubenstein, J.L., Chen,B., 2011. Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities dur-ing neocortical development. J. Neurosci. 31, 549–564.

edina, L., Legaz, I., Gonzalez, G., De Castro, F., Rubenstein, J.L., Puelles, L., 2004.Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distin-guish ventral and lateral pallial histogenetic divisions in the developing mouseclaustroamygdaloid complex. J. Comp. Neurol. 474, 504–523.

eyer, G., 2010. Building a human cortex: the evolutionary differentiation ofCajal–Retzius cells and the cortical hem. J. Anat. 217, 334–343.

eyer, G., Goffinet, A.M., Fairen, A., 1999. What is a Cajal–Retzius cell? A reassess-ment of a classical cell type based on recent observations in the developingneocortex. Cereb. Cortex 9, 765–775.

eyer, G., Perez-Garcia, C.G., Abraham, H., Caput, D., 2002. Expression of p73 andReelin in the developing human cortex. J. Neurosci. 22, 4973–4986.

eynert, T., 1868. Der Bau der Großhirnrinde und seine örtlichen Verschieden-heiten nebst einem pathologisch-anatomischen Korollarium. Vierteljahresschr.Psychiatr.

illet, S., Campbell, K., Epstein, D.J., Losos, K., Harris, E., Joyner, A.L., 1999. A role forGbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature401, 161–164.

olnar, Z., Cheung, A.F., 2006. Towards the classification of subpopulations of layer
V pyramidal projection neurons. Neurosci. Res. 55, 105–115.
olyneaux, B.J., Arlotta, P., Fame, R.M., MacDonald, J.L., MacQuarrie, K.L., Mack-lis, J.D., 2009. Novel subtype-specific genes identify distinct subpopulations ofcallosal projection neurons. J. Neurosci. 29, 12343–12354.


Molyneaux, B.J., Arlotta, P., Hirata, T., Hibi, M., Macklis, J.D., 2005. Fezl is requiredfor the birth and specification of corticospinal motor neurons. Neuron 47,817–831.

Montiel, J.F., Molnar, Z., 2013. The impact of gene expression analysis on evolvingviews of avian brain organization. J. Comp. Neurol. 521, 3604–3613.

Montiel, J.F., Wang, W.Z., Oeschger, F.M., Hoerder-Suabedissen, A., Tung, W.L.,Garcia-Moreno, F., Holm, I.E., Villalon, A., Molnar, Z., 2011. Hypothesis on thedual origin of the mammalian subplate. Front. Neuroanat. 5, 25.

Monuki, E.S., Porter, F.D., Walsh, C.A., 2001. Patterning of the dorsal tele-ncephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron 32,591–604.

Muzio, L., Di Benedetto, B., Stoykova, A., Boncinelli, E., Gruss, P., Mallamaci, A., 2002.Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical pri-mordium. Cereb. Cortex 12, 129–139.

Muzio, L., Mallamaci, A., 2005. Foxg1 confines Cajal–Retzius neuronogenesis andhippocampal morphogenesis to the dorsomedial pallium. J. Neurosci. 25,4435–4441.

Naumann, R.K., Anjum, F., Roth-Alpermann, C., Brecht, M., 2012. Cytoarchitecture,areas, and neuron numbers of the Etruscan shrew cortex. J. Comp. Neurol. 520,2512–2530.

Nieto, M., Monuki, E.S., Tang, H., Imitola, J., Haubst, N., Khoury, S.J., Cunningham, J.,Gotz, M., Walsh, C.A., 2004. Expression of Cux-1 and Cux-2 in the subventric-ular zone and upper layers II–IV of the cerebral cortex. J. Comp. Neurol. 479,168–180.

Noctor, S.C., Flint, A.C., Weissman, T.A., Dammerman, R.S., Kriegstein, A.R., 2001.Neurons derived from radial glial cells establish radial units in neocortex. Nature409, 714–720.

Nomura, T., Gotoh, H., Ono, K., 2013. Changes in the regulation of cortical neurogene-sis contribute to encephalization during amniote brain evolution. Nat. Commun.4, 2206.

Nomura, T., Takahashi, M., Hara, Y., Osumi, N., 2008. Patterns of neurogenesis andamplitude of Reelin expression are essential for making a mammalian-typecortex. PLoS ONE 3, e1454.

Ogawa, M., Miyata, T., Nakajima, K., Yagyu, K., Seike, M., Ikenaka, K., Yamamoto, H.,Mikoshiba, K., 1995. The reeler gene-associated antigen on Cajal–Retzius neu-rons is a crucial molecule for laminar organization of cortical neurons. Neuron14, 899–912.

Oliver, G., Wehr, R., Jenkins, N.A., Copeland, N.G., Cheyette, B.N., Hartenstein, V.,Zipursky, S.L., Gruss, P., 1995. Homeobox genes and connective tissue patterning.Development 121, 693–705.

Pani, A.M., Mullarkey, E.E., Aronowicz, J., Assimacopoulos, S., Grove, E.A., Lowe,C.J., 2012. Ancient deuterostome origins of vertebrate brain signalling centres.Nature 483, 289–294.

Parr, B.A., Shea, M.J., Vassileva, G., McMahon, A.P., 1993. Mouse Wnt genes exhibitdiscrete domains of expression in the early embryonic CNS and limb buds.Development 119, 247–261.

Pollard, K.S., Salama, S.R., Lambert, N., Lambot, M.A., Coppens, S., Pedersen, J.S., Katz-man, S., King, B., Onodera, C., Siepel, A., Kern, A.D., Dehay, C., Igel, H., Ares Jr., M.,Vanderhaeghen, P., Haussler, D., 2006. An RNA gene expressed during corticaldevelopment evolved rapidly in humans. Nature 443, 167–172.

Price, D.J., Aslam, S., Tasker, L., Gillies, K., 1997. Fates of the earliest generated cellsin the developing murine neocortex. J. Comp. Neurol. 377, 414–422.

Price, J., Thurlow, L., 1988. Cell lineage in the rat cerebral cortex: a study usingretroviral-mediated gene transfer. Development 104, 473–482.

Puelles, L., 2011. Pallio-pallial tangential migrations and growth signaling: newscenario for cortical evolution? Brain Behav. Evol. 78, 108–127.

Puelles, L., Kuwana, E., Puelles, E., Bulfone, A., Shimamura, K., Keleher, J., Smiga, S.,Rubenstein, J.L., 2000. Pallial and subpallial derivatives in the embryonic chickand mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1,Nkx-2.1, Pax-6, and Tbr-1. J. Comp. Neurol. 424, 409–438.

Rakic, P., 1988. Specification of cerebral cortical areas. Science 241, 170–176.Rakic, P., 2009. Evolution of the neocortex: a perspective from developmental biol-

ogy. Nat. Rev. Neurosci. 10, 724–735.Rallu, M., Machold, R., Gaiano, N., Corbin, J.G., McMahon, A.P., Fishell, G.,

2002. Dorsoventral patterning is established in the telencephalon ofmutants lacking both Gli3 and Hedgehog signaling. Development 129, 4963–4974.

Regad, T., Roth, M., Bredenkamp, N., Illing, N., Papalopulu, N., 2007. The neuralprogenitor-specifying activity of FoxG1 is antagonistically regulated by CKI andFGF. Nat. Cell Biol. 9, 531–540.

Reid, C.B., Liang, I., Walsh, C., 1995. Systematic widespread clonal organization incerebral cortex. Neuron 15, 299–310.

Reiner, A., Northcutt, R.G., 2000. Succinic dehydrogenase histochemistry reveals thelocation of the putative primary visual and auditory areas within the dorsalventricular ridge of Sphenodon punctatus. Brain Behav. Evol. 55, 26–36.

Retzius, G., 1893. Die Cajal’schen Zellen der Grosshirnrinde beim Menschen und beiSäugetieren. Biologische Untersuchungen. Neue Folge 5, 1–8.

Rice, D.S., Curran, T., 2001. Role of the reelin signaling pathway in central nervoussystem development. Annu. Rev. Neurosci. 24, 1005–1039.

Roth, M., Bonev, B., Lindsay, J., Lea, R., Panagiotaki, N., Houart, C., Papalopulu, N., 2010.FoxG1 and TLE2 act cooperatively to regulate ventral telencephalon formation.

Rouaux, C., Arlotta, P., 2013. Direct lineage reprogramming of post-mitotic callosalneurons into corticofugal neurons in vivo. Nat. Cell Biol. 15, 214–221.

Roy, A., Gonzalez-Gomez, M., Pierani, A., Meyer, G., Tole, S., 2013. Lhx2 regulates thedevelopment of the forebrain hem system. Cereb. Cortex 24, 1361–1372.













































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































urosc

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S


aganich, M.J., Vega-Saenz de Miera, E., Nadal, M.S., Baker, H., Coetzee, W.A., Rudy,B., 1999. Cloning of components of a novel subthreshold-activating K(+) chan-nel with a unique pattern of expression in the cerebral cortex. J. Neurosci. 19,10789–10802.

ahara, S., O’Leary, D.D., 2009. Fgf10 regulates transition period of cortical stemcell differentiation to radial glia controlling generation of neurons and basalprogenitors. Neuron 63, 48–62.

chaeren-Wiemers, N., Andre, E., Kapfhammer, J.P., Becker-Andre, M., 1997. Theexpression pattern of the orphan nuclear receptor RORbeta in the develop-ing and adult rat nervous system suggests a role in the processing of sensoryinformation and in circadian rhythm. Eur. J. Neurosci. 9, 2687–2701.

ekine, K., Kawauchi, T., Kubo, K., Honda, T., Herz, J., Hattori, M., Kinashi, T., Naka-jima, K., 2012. Reelin controls neuronal positioning by promoting cell-matrixadhesion via inside-out activation of integrin alpha5beta1. Neuron 76, 353–369.

ekine, K., Kubo, K., Nakajima, K., 2014. How does Reelin control neuronal migrationand layer formation in the developing mammalian neocortex? Neurosci. Res.,http://dx.doi.org/10.1016/j.neures.2014.06.004.

eoane, J., Le, H.V., Shen, L., Anderson, S.A., Massague, J., 2004. Integration of Smadand forkhead pathways in the control of neuroepithelial and glioblastoma cellproliferation. Cell 117, 211–223.

hen, Q., Wang, Y., Dimos, J.T., Fasano, C.A., Phoenix, T.N., Lemischka, I.R., Ivanova,N.B., Stifani, S., Morrisey, E.E., Temple, S., 2006. The timing of cortical neurogen-esis is encoded within lineages of individual progenitor cells. Nat. Neurosci. 9,743–751.

himamura, K., Hartigan, D.J., Martinez, S., Puelles, L., Rubenstein, J.L., 1995. Longi-tudinal organization of the anterior neural plate and neural tube. Development121, 3923–3933.

himamura, K., Rubenstein, J.L., 1997. Inductive interactions direct early regional-ization of the mouse forebrain. Development 124, 2709–2718.

hitamukai, A., Konno, D., Matsuzaki, F., 2011. Oblique radial glial divisions in thedeveloping mouse neocortex induce self-renewing progenitors outside the ger-minal zone that resemble primate outer subventricular zone progenitors. J.Neurosci. 31, 3683–3695.

imeone, A., Gulisano, M., Acampora, D., Stornaiuolo, A., Rambaldi, M., Boncinelli, E.,1992. Two vertebrate homeobox genes related to the Drosophila empty spiraclesgene are expressed in the embryonic cerebral cortex. EMBO J. 11, 2541–2550.

mart, I.H., Dehay, C., Giroud, P., Berland, M., Kennedy, H., 2002. Unique morpho-logical features of the proliferative zones and postmitotic compartments of theneural epithelium giving rise to striate and extrastriate cortex in the monkey.Cereb. Cortex 12, 37–53.

oda, T., Nakashima, R., Watanabe, D., Nakajima, K., Pastan, I., Nakanishi, S., 2003.Segregation and coactivation of developing neocortical layer 1 neurons. J. Neu-rosci. 23, 6272–6279.

ommer, L., Ma, Q., Anderson, D.J., 1996. Neurogenins, a novel family ofatonal-related bHLH transcription factors, are putative mammalian neuronaldetermination genes that reveal progenitor cell heterogeneity in the developingCNS and PNS. Mol. Cell. Neurosci. 8, 221–241.

oriano, E., Del Rio, J.A., 2005. The cells of Cajal–Retzius: still a mystery one centuryafter. Neuron 46, 389–394.

rinivasan, K., Leone, D.P., Bateson, R.K., Dobreva, G., Kohwi, Y., Kohwi-Shigematsu,T., Grosschedl, R., McConnell, S.K., 2012. A network of genetic repression andderepression specifies projection fates in the developing neocortex. Proc. Natl.Acad. Sci. U.S.A. 109, 19071–19078.

taiger, J.F., Flagmeyer, I., Schubert, D., Zilles, K., Kotter, R., Luhmann, H.J., 2004.Functional diversity of layer IV spiny neurons in rat somatosensory cortex: quan-titative morphology of electrophysiologically characterized and biocytin labeledcells. Cereb. Cortex 14, 690–701.

triedter, G.F., Marchant, T.A., Beydler, S., 1998. The neostriatum develops as part ofthe lateral pallium in birds. J. Neurosci. 18, 5839–5849.

tumm, R.K., Zhou, C., Ara, T., Lazarini, F., Dubois-Dalcq, M., Nagasawa, T., Hollt,
V., Schulz, S., 2003. CXCR4 regulates interneuron migration in the developingneocortex. J. Neurosci. 23, 5123–5130.
uda, Y., Hossain, Z.M., Kobayashi, C., Hatano, O., Yoshida, M., Matsuo, I., Aizawa, S.,2001. Emx2 directs the development of diencephalon in cooperation with Otx2.Development 128, 2433–2450.

ience Research 86 (2014) 37–49 49

Suda, Y., Matsuo, I., Aizawa, S., 1997. Cooperation between Otx1 and Otx2 genes indevelopmental patterning of rostral brain. Mech. Dev. 69, 125–141.

Suzuki, I.K., Kawasaki, T., Gojobori, T., Hirata, T., 2012. The temporal sequence of themammalian neocortical neurogenetic program drives mediolateral pattern inthe chick pallium. Dev. Cell 22, 863–870.

Takiguchi-Hayashi, K., Sekiguchi, M., Ashigaki, S., Takamatsu, M., Hasegawa, H.,Suzuki-Migishima, R., Yokoyama, M., Nakanishi, S., Tanabe, Y., 2004. Generationof reelin-positive marginal zone cells from the caudomedial wall of telencephalicvesicles. J. Neurosci. 24, 2286–2295.

Tao, W., Lai, E., 1992. Telencephalon-restricted expression of BF-1, a new mem-ber of the HNF-3/fork head gene family, in the developing rat brain. Neuron 8,957–966.

Teissier, A., Griveau, A., Vigier, L., Piolot, T., Borello, U., Pierani, A., 2010. A novel tran-sient glutamatergic population migrating from the pallial–subpallial boundarycontributes to neocortical development. J. Neurosci. 30, 10563–10574.

Teissier, A., Waclaw, R.R., Griveau, A., Campbell, K., Pierani, A., 2012. Tangentiallymigrating transient glutamatergic neurons control neurogenesis and mainte-nance of cerebral cortical progenitor pools. Cereb. Cortex 22, 403–416.

Theil, T., Aydin, S., Koch, S., Grotewold, L., Ruther, U., 2002. Wnt and Bmp signallingcooperatively regulate graded Emx2 expression in the dorsal telencephalon.Development 129, 3045–3054.

Tissir, F., Goffinet, A.M., 2003. Reelin and brain development. Nat. Rev. Neurosci. 4,496–505.

Tissir, F., Lambert De Rouvroit, C., Sire, J.Y., Meyer, G., Goffinet, A.M., 2003. Reelinexpression during embryonic brain development in Crocodylus niloticus. J. Comp.Neurol. 457, 250–262.

Tissir, F., Ravni, A., Achouri, Y., Riethmacher, D., Meyer, G., Goffinet, A.M., 2009.DeltaNp73 regulates neuronal survival in vivo. Proc. Natl. Acad. Sci. U.S.A. 106,16871–16876.

Toresson, H., Martinez-Barbera, J.P., Bardsley, A., Caubit, X., Krauss, S., 1998. Con-servation of BF-1 expression in amphioxus and zebrafish suggests evolutionaryancestry of anterior cell types that contribute to the vertebrate telencephalon.Dev. Genes Evol. 208, 431–439.

Ulinski, P.S., 1986. Organization of corticogeniculate projections in the turtle, Pseude-mys scripta. J. Comp. Neurol. 254, 529–542.

Villar-Cervino, V., Marin, O., 2012. Cajal–Retzius cells. Curr. Biol. 22, R179.von Frowein, J., Campbell, K., Gotz, M., 2002. Expression of Ngn1, Ngn2, Cash1, Gsh2

and Sfrp1 in the developing chick telencephalon. Mech. Dev. 110, 249–252.von Frowein, J., Wizenmann, A., Götz, M., 2006. The transcription factors Emx1 and

Emx2 suppress choroid plexus development and promote neuroepithelial cellfate. Dev. Biol. 296, 239–252.

Walsh, C., Cepko, C.L., 1988. Clonally related cortical cells show several migrationpatterns. Science 241, 1342–1345.

Walsh, C., Cepko, C.L., 1992. Widespread dispersion of neuronal clones across func-tional regions of the cerebral cortex. Science 255, 434–440.

Yoneshima, H., Yamasaki, S., Voelker, C.C., Molnar, Z., Christophe, E., Audinat, E.,Takemoto, M., Nishiwaki, M., Tsuji, S., Fujita, I., Yamamoto, N., 2006. Er81 isexpressed in a subpopulation of layer 5 neurons in rodent and primate neocor-tices. Neuroscience 137, 401–412.

Yoshida, M., Assimacopoulos, S., Jones, K.R., Grove, E.A., 2006. Massive loss ofCajal–Retzius cells does not disrupt neocortical layer order. Development 133,537–545.

Yoshimura, Y., Dantzker, J.L., Callaway, E.M., 2005. Excitatory cortical neurons formfine-scale functional networks. Nature 433, 868–873.

Yu, Y.C., Bultje, R.S., Wang, X., Shi, S.H., 2009. Specific synapses develop preferentiallyamong sister excitatory neurons in the neocortex. Nature 458, 501–504.

Yu, Y.C., He, S., Chen, S., Fu, Y., Brown, K.N., Yao, X.H., Ma, J., Gao, K.P., Sosinsky, G.E.,Huang, K., Shi, S.H., 2012. Preferential electrical coupling regulates neocorticallineage-dependent microcircuit assembly. Nature 486, 113–117.

Yun, K., Potter, S., Rubenstein, J.L., 2001. Gsh2 and Pax6 play complementary roles
in dorsoventral patterning of the mammalian telencephalon. Development 128,193–205.
Zhong, Y., Takemoto, M., Fukuda, T., Hattori, Y., Murakami, F., Nakajima, D.,Nakayama, M., Yamamoto, N., 2004. Identification of the genes that areexpressed in the upper layers of the neocortex. Cereb. Cortex 14, 1144–1152.



























































































































































































































































































































































































































































































































































































































































































































































































































































































neuronal subtype specification in establishing mammalian ... · areas (noctor et al., 2001; rakic,...

Documents