transcriptional mechanisms of developmental cell cycle arrest

8/11/2019 Transcriptional Mechanisms of Developmental Cell Cycle Arrest

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The fact that cells provided with plenty of nutrients do not

proliferate is rather a late event in evolutionary terms given itsappearance with the emergence of multicellularity. These evolu-tionary arguments have led some scientists to adopt the view that

proliferation is the default cellular state in multicellular as well as

unicellular organisms. For unicellular organisms, and even if theycanengage in many kinds ofinteractions(forexample, thequorumsensing phenomenon [2]), this is not in doubt (also, see [3]). Theview that proliferation is the default state of allcellsis less common

amongst developmental and cancer biologists despite being force-fully proposed and tested by Soto and Sonnenschein [36]. Fromthis perspective, a mitogenic effect would ultimately consist inremoving the brakes from a proliferative default state [7]. The

central questions in proliferation control are therefore related to

negative regulation: how is proliferation actively inhibited duringembryogenesis, and also how is this arrested state maintained inadult organisms?

In the developmental history of a cell, cessation of mitosis isa crucial event, and its consequences are manifold. Constraints oncytoskeleton organisationmake cell cycle exit mandatoryfor cellu-lar structural specialisations, a point recognised long ago [8]. Buss

went even as far as to consider that incompatibility between celldivision and movement (by flagella or cilia) is at the root of the

emergence of multicellularity [9].Another consequence of arresting the cell cycle at precise space

and time points in development is to determine the size of meta-zoan organisms, and organs within organisms. Control of sizesignificantly depends on cell proliferation. Size is one of the mostevolutionary plastic parameters in metazoan biology [10,11]. Huge

differences in size exist in the animal kingdom, not only betweendistantly related metazoans, say a mite and a whale, but alsobetween animals belonging to the same clade, and thus shar-ing the same developmental Bauplan: for example, in the avian

clade, size ranges from 1.5 g (some hummingbirds) to 130 kg (theostrich); and amongst beetles (clade Coleoptera), from 300m(some Nanosellini [12]) to about 17cm (Titanus giganteus, Ceram-bycidae). Regardless, all metazoans, be they a minute beetle or a

whale, begin their life cycle as a single cell (the egg). Moreover, upto the axis elongation stage, all metazoan embryos are comparableinsize (no morethan 1 mm), probably due to very tight constraintsin patterning mechanisms based on morphogen diffusion [8], while

being made ofactively proliferating cells: DCCE is thus secondary indevelopment as it is in evolution. The final size, and to some extentshape, of an organism is determined by when (after how manycycles) andwhere(in thedifferentorgans) DCCE takes place.Eutelic

animals, such as the nematodes, that grow post-embryonically onlyby enlarging their cells are a possible, and partial, exception, andwill not be considered in the frame of this review.

Next, we will deal with some aspects of the molecular mech-

anisms of DCCE, illustrate the gaps in our current knowledge ofthis subject, and describe and discuss the cellular conveyor belts

notion, that we feel could fill some of those gaps. We shall endour discussion by considering whether the developmental mecha-nismsof cell cycle exit persist in adult organisms. All our examplesbelong to the field of nervous system development; however, ourconclusions may well be extended to other tissues.

2. Mechanisms of developmental cell cycle arrest

2.1. The cell cycle machinery

The cell cycle machinery has not significantly changed in uni-cellular and multicellular eukaryotes during evolution. A detailed

discussion of the cell cycle molecular engine [13] is beyond the

scope of this review (Fig. 1). Nonetheless, a few aspects of the

machinery deserve attention to place the subject of DCCE in con-

text. The biochemical switches at the core of the cell cycle controlsystem, i.e., the associations between the cyclin-dependent kinases(Cdks) and their cyclin partners, are essentially the same in alleukaryotic cells; the differences are mostly due to variations in

the number of members in these families. These variations seem tohave happened very early forthe cyclins [14,15], and more recentlyfor the Cdks, resulting in a partial functional overlap between theseproteins [16]. The high degree of conservation at the core of the

cycle engine is classically illustrated by the rescue of yeast cdc28mutants by a human Cdk1 gene [17].

When turning more specifically tothe proteins knownto directlyinteract withthe core cell cycle machineryand to have an inhibitoryeffect on it, i.e., the cyclin-dependent kinase inhibitors (ckis) andRb proteins [18, Fig. 1], again conservation seems to be the rule.Members of the Rb and Cip/Kip protein families can be foundin all metazoans, albeit again in variable numbers. There is one

Cip/Kip and two Rb proteins in the Drosophila and sea urchingenomes, and this may correspond to the ancestral metazoan sit-uation [19]. On the other hand, these families have expanded inthe vertebrate clade. An interesting exception is the INK4 fam-

ily of ckis (p16Ink4, p14Ink4, p18Ink4, p19Ink4; now denominatedCdkn2a, Cdkn2b, Cdkn2c and Cdkn2d, respectively) which is prob-

ably vertebrate-specific. To date, no INK4 orthologues have beenfound in thesea urchin genome [19], or in protostome genomes. In

line withwhat is observed forthe Cdks proteins,expansion of theseinhibitory proteins families in vertebrates seems to have resultedin, at least partial, functional redundancy, as evidenced by the phe-notypes of mouse multiple mutants [18]. This may suggest that

there is room forevolutionary innovation at, or near, the core of thecell cycle machinery, as evidenced by the apparition of the INK4family in vertebrates, where its role is quite important [2022].However, it is unlikely that by looking at this core level only one

would understand how DCCE is regulated in different contexts anddifferentorganisms. Thevarious signals to arrestthe cycle mayulti-mately impinge on this machinery [23,24], butDCCE is so plasticinmetazoans that the regulative mechanisms may have to be looked

for at places other than the Cdks, cyclins, Rb and Cdkis families.

2.2. The signalling pathways

Intercellular signalling pathways in metazoan development arefrequently presented with a final arrow pointing to cell prolifer-ation. However, it is widely acknowledged that most signallingpathways induce both developmental cell cycle exit and non-exit

(maintenance of proliferative state) depending on the context, thedevelopmentalstage,or even the species considered. The literatureon thistopicis quite extended,and therefore, we have selected onlya few examples to illustrate our point:

- Shh signalling drives cell proliferation in the mouse cerebellum(produced by Purkinje cells; active on granule cell progenitors[25]); however, this signalling acts as a cell cycle exit signal inthe zebrafish retina (produced by retinal amacrine and ganglioncells; active on retinal progenitors [26,27]). In this later case, the

situation is even more complex, since Shh signalling has oppositeeffects in mouse where it increases mitotic index in retinal pro-genitors [28] while it doesnot in zebrafish.A possible explanationhere might lie in timing problems, which occur when comparing

different developmental stages in different species [29].- Similarly, the Wnt/-catenin pathway drives proliferation in

most tissues, for example in the neural retina [30]. However,it promotes differentiation towards particular cell fates in the

peripheral (non-neural) retina [31,32] as well as in the neuralcrest [33].


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Fig. 1. Thecell cycle engineof mammaliancells andits main negative regulators.

The cell cycle is driven by the sequential association of Cdks and cyclins: in G1 (growth phase): cyclin D, Cdk 4 and 6; in S (DNA synthesis phase): cyclin A, Cdk 1 and 2; in

G2 (gap phase):cyclin A, Cdk1; in M (mitosis phase): cyclinB, Cdk1. Each Cdkcyclin complex is thus specific of a phaseof thecycle. Thedecisionto enter a newcycle, or to

arrest proliferation, is taken in G1.Prolonged, or terminal, exit from thecycle is often denoted as G0.

The INK4 family members actby competing with cyclins D forbinding with Cdk 4/6. They thus prevent the formation of activecyclinCdk complexes, and inhibit cell cycle

(re-)entry.

The Cip/Kip family members have a dual action: although they are necessary for the formation of active cyclin DCdk complexes, they inhibit cyclin E/ACdk 2 complexes,

and thus block cell cycle (re-)entry.

Themembersof thepRB family of pocket proteins (Rb, p107 and p130) aremajor negative regulators of proliferation through their interactionswith theE2F family. These

transcriptional regulators control theexpression of manylateG1, or G1/S genes, theproductsof whichare necessary forcycle progression.pRB binds to thetranscriptionalactivation domains of activator E2Fs and blocks their action. Other members of the pRB proteins bind to repressor E2Fs and thus stimulate the formation of chromatin

structures that inhibit gene expression.

Complex reciprocal interactions take place between these molecules. In addition, numerousintracellularand intercellular signalling pathways and moleculesimpinge upon

the cycle machinery, in a cell type- and developmental stage-dependentmanner. Although many such interactions have been reported, details are most often lacking. Thisscheme is intended as a simplified and general guide only.

- The Fgf signalling pathway regulates proliferation during devel-opment. It cando it positively,as theexpressionof a constitutivelyactive form of the Fgf receptor Fgfr3 correlates with an increaseof neural progenitor proliferation, and with an overgrowth of the

cerebral cortex in mice [34]; there are also negative correlations,since deletion ofFgf15 removes the brakes and induces an over-growth in the mouse dorsal midbrain [35]. Also, Fgf signallingblocks proliferation and induces differentiation of granule cell

progenitors in the developing mouse cerebellum [36], an effectcontrary to that ofShh signalling on these cells (see above). There

is a recurrent pattern in such studies, i.e., progenitor cells receive,and integrate, multiple signals with either similar or opposite

effects.- BMPs, other well-known signalling molecules, canact as inducers

of cell cycle exit and differentiation, as in the developing dorsalspinal cord progenitors [37] where they counteract a Wnt prolif-

erative signal; alternatively, they have also been claimed to driveproliferation, as in the development of the cerebellar granule cellprogenitors [38].

- Additional examples of these conflicting effects on cell prolifer-

ation arrest can be found both in the CNS and in other organs.Such situations seem to be the rule. Some exceptions appearto be the IGF pathway, and the Hippo/Salvador/Yorkie pathwaywhich have been shown to be importantin organ size control, and

theiractivationalways seems to drivecell proliferation [8,3941],

although, again, an opposed outcome has been reported [42]. Inthe case of the IGF pathway, its importance in size control andproliferation regulationmakes sense because this pathway is inti-mately linked to the TOR one, a critical sensor of the metabolic

state in metazoans [43]. It is acknowledgedthat proliferation can-not take place if minimum metabolic requirements are unmet.

In summary, the conclusions that can safely be drawn from the

enormous mass of reports on signalling pathways in DCCE are:

- most signalling pathwayscan induce orblockDCCE,depending onthe organ, the stage of development, and the species considered.- signalling pathways never act alone, but in combination. The

decision to exit the cycle is, at least in part, the outcome of aprocess of integrating and weighting multiple signals that fluc-

tuate through time. The examples of the cerebellar granule cellprogenitors,where at least three pathways (Wnt, Fgf, Bmp) inter-act, is but a case in point; the phenomenon is quite general, inneural development as well as in any other developing organ.

These conclusions render a signalling pathway approach ofDCCE in vivo extremely difficult to fully evaluate. While studiesdealing with the role of a single signalling pathway are common-

place, those dealing with two signals are uncommon, and thosetaking into account three or more are quite rare indeed.


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2.3. Downstream the signalling pathways

Vidal and Koff[18] have pointed out that how the various sig-nals impinge on the cell cycle engine remains poorly understood.It is well known that various transduction pathways act upon the

cell cycle machinery, for example on the transcriptional levels of

cdc25, N-myc, cyclins, and especially ofcyclins D, with are impor-tant effectors in the decision to enter or not a new cycle (Fig. 1).This is documented for FGF and Shh pathways in the chick spinal

cord [44], the Xenopus retina [45], the mouse midbrain-hindbrainregion [46], diencephale [47] and cerebellum [48], among manyexamples. However, the molecular details of these regulations arepoorly known in vivo. There is a huge amount of work, for instance,

on regulation of proliferation by transcription factors (TFs). Moreoften than not, the effects are again dual, depending on the cellu-lar context and the developmental stage. As an example, the wellknown paired-box factorPax6 has been described as inducing pro-

liferationin earlyretinal progenitors[49,50], whilehaving oppositeeffects [51] and as been required for differentiation [52,53]. Thisappears to be the situation for most if not all TFs studied [54]. Itshould also be emphasized that in these studies, it is generally not

known whether the effects of TFs on the cell cycle machinery aredirect or not.

Moreover, it is clear that TFs act in combination in all these sit-uations; additional evidence for this comes from the fact that the

cis-regulatory regions of the cell cycle machinery genes are quitelong and complex [55].

A further complication comes from the difficulty to experi-mentally distinguish the regulation of DCCE on one hand, and of

differentiationper se (i.e., acquisition of a given phenotype) on theother hand. Such dual effects have been documented for severalgenes, including various transcription factors, but also cell cycleregulators like p27Kip1, andmanyothermoleculeslike,for example,

BM88/Cend1 [56].Finally, while this brief discussion is focused on transcriptional

mechanisms, it is clear that other cellular processes beyond thescope of this review have a profound effect on the regulation

of DCCE, such as chromatin structure changes [57] and post-translational modifications [58]. Faced with such complexity, arethere other ways to tackle the problem of DCCE?

2.4. Genes involved in DCCE

A possibility in this direction would be to take a nave view atthe genes possibly implicated in DCCE; by a nave view, we mean

without any prerequisite about the precise mechanism of theiraction, or the molecular pathway they are part of, or the cellularcontext where they are active. This could be done by looking atgenomic databases for specifically annotated genes. Such a search

yields vast numbers of genes: for example, as of July 2011, in GeneOntology (www.geneontology.org/), 1037 genes were labelled as

Negative regulators of growth and 1992 genes as Negative reg-ulators of cell proliferation. It would be of interest to look at whatis known about the role of these genes in development, or evensimply at their expression pattern in developing organisms. Whendoing so the relative paucity of such studies is striking. This is pic-

tured in Fig. 2, which provides a comparison of the availability ofdevelopmental data for Negative regulators of cell proliferation,on one hand, and for Transcription factors, on the other hand.It illustrates the acknowledged point that, until recently, develop-

mental biologists mostly focused on patterningmechanisms andgenes. This does not necessarily imply that little is known of thesenegative regulators of cell proliferation. They are mostly studied

in vitro, and especially in tumoral cell cultures. Whether or not the

data thus gathered are relevant for developmental studies is rather

unclear.

A sort of bias is even more obvious when one takes into

account comparative/evolutionary aspects of inhibitory pathways.The developmental regulator genes have been, and continue tobe analysed in evolutionary (evo-devo) contexts; however, thenegative regulators of growth/proliferation remain mostly disre-

garded, although studies on size control have been undertaken inthe traditional model organisms [8,3941].

3. Cellular conveyor belts in studies of DCCE

In this section, we will propose the comparative study ofcellu-lar conveyor belts as a possible tool to study DCCE in metazoans.This kind of study is obviously only one of many possible, perhapsnecessary, approaches that carry a promising potential.

3.1. What is it meant by a cellular conveyor belt (CCB)?

ACCBis anorgan, ora partof anorganthat has a balancedgrowthpattern so that, during development, there is no mixing between

proliferative cells and cells that exit the cycle. Typically, these arepolarised growing organs which bear at one pole (or extremity) azone of actively dividing progenitors, followed by a zone of cells

exiting the cycle, followed by a zone of differentiating cells.

3.2. Are there examples of CCBs documented?

Fig. 3 presents a few examples of CCBs. The intestinal crypt of

mammals (Fig. 3A) [59], and presumably of all vertebrates, pro-vides an example of a permanent conveyor belt which functionsthroughout life. The retina of teleostean fishes and amphibians,both during development and adult life, is another classical exam-

ple (Fig. 3B) [60]. The fish optic tectum (a cortical structure ofthe dorsal midbrain), our preferred model, also functions as a CCBduring embryonic development and in adults (Fig. 3C) [61], as doc-umented in several species of teleosts [62,63]. The male gonads of

some teleosts, where that process is called cystic growth,also grow

following a conveyor belt pattern [64,65]. All these examples arefrom vertebrates.Well documented casesare rarerin non-chordatedeuterostomes, protostomes and non-bilaterians. However, it is

likely that CCBs are present in other species as well. Indeed, innon-bilaterians, the growth of cnidarian tentacles provides a clearexample of a conveyor belt situation [66], as do the tentacle rootof ctenophores [67]. In lophotrochozoans, the cerebral ganglia of

snails also grows following a conveyor belt model [68]. In con-clusion, CCBs can be found in many different tissues and in manydifferent organisms. In different species, the same (i.e., homolo-gous) organs may grow as CCBs or otherwise: the optic tectum

provides a clear example, as it grows as a conveyor belt in teleosts,but quite differently in mammals andbirds [61]. The resulting adultstructures are nevertheless both evolutionarily homologues, and

functionally similar, meaning that there are different developmen-tal ways to achieve the same end during adulthood. Conveyor beltsare essentially useful models for the study of developmental cellproliferation.

3.3. Can other examples of CCBs be found?

CCBs may be easily characterised by the administration (byinjection, bathing or feeding) of a dose of a thymidine ana-

logue (BrdU, IdU, CldU, Edu) to developing animals. Sacrificing theanimals a few hours later would identify the location of the prolif-erating cells; sacrificing them after a chase delay (usually one, or afew days) would allow to determine whether the situation is that

of a conveyor-belt type or not (Fig. 4). This kind of experiment is

feasible in most animal species as long as live embryonic forms are
http://www.geneontology.org/http://www.geneontology.org/


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Fig. 2. Comparison between the availability of developmental data for Negative regulators of cell proliferation and for Transcription factors.

From Gene Ontology and Swissprot websites, we randomly retrieved two lists of about1000 genes belongingto these twoannotated categories.

Then we randomly picked 50 genes from each of the two lists and carefully checked the associated literature in PubMed; we then repeated this process of random picking

twice. Theresults were grouped and displayed in three categories:

- genes for which no developmental data (expression pattern or function, for example, mutant developmental phenotype) are available in

any species;- genes for which developmental data (of any kind) are available in only one species;- genes for which developmental data (of any kind) are available in at least two species.

available. Adults might also be used in species in which animalsgrow continuously throughout life (like most fishes or molluscs).

3.4. What is the specific interest of CCBs in DCCE studies?

The main interest of CCBs is to provide systems where it wouldbe easy to quickly evaluate if a given gene is potentially involvedin DCCE, on the basis of an in situ hybridisation (ISH). We have

verified the predictive value of these simple expression patterns[69,70]. We indeedshowed that overexpression,by mRNA injectionin embryos at one- or two-cell stages, of two molecules identi-

fied by their restricted expression in the OT cell cycle exit zone,

GADD45 [69] and Insm1 [70], slowed down cell divisions in earlymedakaembryos. These genes were thus demonstrated to be novelnegative regulators of proliferation in vivo. More recently, we have

undertaken an ISH screen aimed at identifying genes involved in

Fig. 3. Schematic representations of three examples of cellular conveyor belts. (A) Optic tectum of a teleost fish; (B) retinaof a teleost fishor a frog; (C) intestinal crypts ofa mammal. The stem cell zones are in red, the zones ofactively dividing progenitors are in yellow, the cell cycle exitzones are in green, the zones ofdifferentiated cells are in

blue. The open arrows indicate the direction of the cellular conveyor belts movements. cb: ciliary body; gcl: ganglion cell layer; iinl: inner part of the inner nuclear layer;

ic: intestinal crypt (Lieberkhncrypt); iv:intestinal villosity; L: lens; oinl: outer part of theinner nuclear layer;OT: optic tectum; Pc:Paneth cells;pgz: periventricular grey

layer; prl: photoreceptor layer; Teg: tegmentum (ventral midbrain).


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Fig. 4. How to recognize a cellular conveyor belt. Comparison of the morphogenesis of the forebrain (F) and retina (R) in a teleost fish. (A) After administration of a BrdU

pulse to a 3-day-old fish embryo, the proliferative zones are labelled: the ventricular zone of the forebrain (green arrow) and the ciliary marginal zone of the retina (pink

arrows). (B) Same experiment, but with a chase (survival time) of 5 days. The post-mitotic, Brdu labelled, cells become dispersed in the forebrain (green arrow), whereas

they remain grouped in the retina (pink arrows). The retina grows according to a conveyor-belt pattern while the forebrain does not. Cb: ciliary body; F: forebrain; L: lens;

on: optic nerve.

DCCE in the developing fish optic tectum. The rationale was tostart from a list of mammalian negative regulators of growth ortumour suppressors, and next examine the expression pattern

of their orthologues in the embryonic fish OT. From a starting listof about 250 genes, we found 26 genes expressed in the OT witha pattern suggesting an involvement in DCCE (unpublished data).Moreover, in situations like that of the medaka OT, where the con-

veyor belt functions very precisely with absolutely no mixing ofcells with different birthdates, it is possible to infer the temporalsequence of transcriptional activation of several genes from their

spatial expression pattern (Fig. 5). Very few functional or molecu-

lar studies on CCB systems are availableat present. However, it hasbeen shown that the canonical Wnt pathway is involved in prolif-eration regulation in the postembryonic Xenopus retina, a typicalCCB model [71].

Studies of DCCE with CCE models will also likely benefit fromthe recent technological breakthroughs in the fields of (a) lasermicrodissection and (b) deep sequencing from small tissue sam-ples. These novel technological features will indeed allow the

dissection of small populations of actively dividing progenitors

versus small populations of cell exiting the cycle, and to comparetheir transcriptomes in a well defined developmental context.

4. Conclusions: cell cycle arrest beyond embryogenesis

By accepting that proliferation is the default cellular state of allcells, it becomes axiomatic that a cell cycle arrest must occur at

some point during development, but it also should be maintainedthereafter. Still, this arrest could be subsequently reverted. Whatwould be the status of cells that have exited the cycle, in other

words, that stay in G1 for a very long time, or are in G0? Cellsenter quiescence or differentiation, and indeed these states canbe distinguished; at the cellular level, it has long been known, forexample, that, in vertebrates, fibroblasts are less differentiated

than neurons, or muscular fibres. They can relatively easily revertto a proliferative state, and therefore the term quiescence seemsfit for such cells. Moreover, in recent years these situations havebegun to be described at the molecular level, resulting in bet-

ter definitions of these various cellular states [72]. In the case of

fibroblasts and fibroblast-like cells, then, it could be admitted that

they are only transiently, or provisionally, in a non-proliferativestate.

Equally relevant is the case of adult stem cells: it has been pro-

posed that they represent partially arrested cells, since they docycle, but very slowly [73]. It can be said that these cells are prolif-erative, but with weak brakes on.

Thecase of theso-called terminally differentiatedcellsis more

problematic. It is assumed that cells, such as neurons, are lockedin a post-mitotic state and require nothing to remain so; in otherwords, there would be no way for such cells to revert to a prolifer-ative state. However, this assumption has been challenged when it

Fig.5. Schematicrepresentationof thedevelopingteleostoptic tectum. Theexpres-

sion domains of three genes potentially involved in DCCE areshown: gene A (black

oblique lines), gene B (pink oblique lines) and gene C (white horizontal lines). The

temporalorderof transcriptional activation ofthesegenescan bededucedfromtheirspatialexpression:ABC.Only themarginal limitof theexpressiondomainsare

considered (vertical arrows) since the central limit may depend on factors such as

mRNA stability. Thecolourcodeof theOTzonesis thesame asin Fig. 1. Open arrows:

direction of the cellular conveyor belt movement.


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transcriptional mechanisms of developmental cell cycle arrest

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