ontogenesis in the cns neurogenesis during embryonic...
TRANSCRIPT
Formation of the neural tube
neural groove
neural groove neural plate
neural crest
notochord neural tube
Tsai et al., Nat Neurosci. 2010 Dec;13(12):1463-71
ve
ntr
icula
r zone
apical
(ventricular)
surface
basal (pial)
surface
cilium
• neuroepithel stem cell [NE (stem) cell]
- radial shape, anchored to pial and ventricular ECM; ventricular cilium
- centrosome localized near the cilium, microtubule + end towards the pia
- nuclear movement based on dynein / kinesin (KIF1A) activity along cell cycle
- apical mitosis: symmetric cell divisions, expansion in cell number/surface
Interkinetic nuclear migration within the ventricular zone
• neuroepithel stem cell [NE (stem) cell; NEC] -> radial glia
Interkinetic nuclear migration within the ventricular zone
- radial shape, anchored to pial and ventricular ECM; ventricular cilium
- centrosome localized near the cilium, microtubule + end towards the pia
- nuclear movement based on dynein / kinesin (KIF1A) activity along cell cycle
- apical mitosis: symmetric / asymmetric cell divisions
Noctor et al.
E30 E45 E31-32 E55 14w
The radial glia (RG)
radiális glia
migráló neuronális
prekurzorok
Rakic P. J. Comp. Neurol. 1972, 145: 61-84
radiális glia
migráló neuronális
prekurzorok
Rakic P. J. Comp. Neurol. 1972, 145: 61-84
Bystron et al; Nat Rev Neurosci. 2008 Feb;9(2):110-22.
VZ: ventricular zone
PP: preplate
SVZ: subventricular zone
CP: cortical plate
IZ: intermedier zone
MZ: marginal zone
SP: subplate
• originally: radial migratory „railway” from the VZ towards the pial surface in the neocortex
„protomap” hypothesis (Rakic)
• transient phenotype, develops into astrocytes
(human)
• transition from NECs, transient neuronal stem cells
(<E11; mouse)
• direct and indirect (via basal progenitors / transient amplifying cells / neuronal precursors / neuronal progenitors) ways of generating neurons – neurogenic phase
• perinatally gliogenic phase: formation of astrocytes / oligodendrocytes
• nestin+; glial features (GLAST, S100, GFAP, vimentin, BLBP)
The radial glia (RG)
Radial glia lineage in the dorsal telencephalon
IP: intermedier progenitor = basal progenitor = transit amplifying cell = neuronal progenitor = neuronal precursor (NPC)
retinoids
CNTF/LIF; TGFb
GABA, Glu
Factors influencing RG’s fate
GABA, (Glu)
Wnt / Shh / Par signaling Notch-Delta [Ca2+]IC
Elias, Kriegstein
proliferative effect synchronisation
differentiation
a long story....
dogma: no neurogenesis within the adult brain
50's: 3H-timidin labeling to mark dividing cells in vivo within the brain
60's, Altman: newborn neurons within the rodent neocortex,
dentate gyrus (DG) and in the olfactory bulb
70-80's, Kaplan: new neurons within the hippocampus survive
for many years and form functional circuits
80's: functional neurogenesis is required for learning new songs (high
vocal center), (Nottebohm)
1992: neurosphere and NSCs isolated from adult rodent brain (Reynolds,
Weiss)
1999: neurosphere and NSCs isolated from adult human brain (Kukekov)
2000- thousands of papers....
1999-2004: who is the neural stem cell??? -> GFAP+ glia cell
J. Neurosci., 2002, 22(3):629–634
Alvarez-Buylla and Garcı´a-Verdugo
Nottebohm
J. Neurosci., 2002, 22(3):624–628
Neurogenesis within the adult brain
songbirds:
high vocal center (striatum)
mammals:
subventricular zone
(SVZ)
hippocampus dentate
gyrus (GD)
subgranular zone (SGZ)
GD Glu-ergic
granule cells
GABAergic inhibitory granule
cells; dopaminergic periglomerular
cells in the olfactory bulb
Adult neural stem cells within the SVZ
SVZ: astrocyte
Nat Rev Neurosci 2003 6 1127
• in vivo: only OB neurogenesis
• in vitro multipotency: neuron,
oligodendroglia, astrocyte can be formed
• differentiation is determined by the local
micro-environment (niche)
ependyma:
noggin production
(niche); cilia
B cell [radial glia-like cell]:
self-renewing, GFAP +
one (or more) cilium towards the lumen
C cell:
fast division, transient amplifying cell
A cell:
committed, migrating neuroblast
RMS: rostral migratory stream
• chain migration of interneurons
RMS: neuronal chain migration
- PSA-NCAM, EphB2 / ephrin-B2, neuregulin / Erb4
• within the OB (olfactory bulb), radial migration starts (reelin)
SVZ neurogenesis – integration of new neurons
neurogenesis within the olfactory
system:
• central: (accessory) olfactory bulb
- granule cell
- periglomerular cell
• periphery: vomeronasal organ
- sensory neurons
SVZ neurogenesis – integration of new neurons
dendro-dendritic
synapses
AOB: accessory olfactory bulb;
DG: dentate gyrus;
LV: lateral ventricle;
MOB: main olfactory bulb;
MOE: main olfactory epithelium;
RMS: rostral migratory stream;
VNO: vomeronasal organ
OSN: olfactory sensory neuron
PG: periglomerular neuron
GC: granule cell (szemcsesejt)
MC: mitral cell
• constant supply of new neurons:
- OSN: derived from MOE precursors, axons are projected into the glomeruli; same receptor – same glomerulus
- PG: dendro-dendritic synapses formed on the mitral cells
- GC: recurrent dendro-dendritic synapses on the lateral dendrites of the mitral neurons (lack of axons)
Functional importance of SVZ neurogenesis
• daily replacement of 1% of neurons within the OB (~97% granule cells)
• constant turnover of sensory neurons -> constant turnover of interneurons
within the (A)OB (new neurons should integrate into the network)
• local networks: processing olfactory
stimuli depending on memory,
pregnancy, behavior...
• critical period for survival between 2-6 weeks (half of new neurons die)
• new neurons: strong inhibitory effects on
the glomeruli (PG neurons) or on the
mitral/tufted cells (granule cells)
B cell (radial astrocyte, type 1 cell):
self-renewal, GFAP +
D cell (type 2 cell):
neuronal progenitor (neuroblast)
G cell:
granule cell
GD granule neuron:
mature Glu-ergic interneuron
Doetsch F. Nat
Neurosci 20036 1127
SGZ: astrocyte Neuron, Vol. 41, 683–686, 2004,
Alvarez-Buylla*, A. Lim
Adult neural stem cells within the SGZ
Adult neural stem cells within the SGZ
• radial astrocytes (B cells) are
directly derived from radial glia (?)
Integration on newly born SGZ neurons
• no synaptic inputs during the first
week for young GCs, only tonic
GABA activation + slow maturation
- GABAA receptors; high [Cl-]IC ->
depolarizing action of tonically
released GABA
- hyperpolarizing GABA acti-
vity develops around 4w
- neuronal activity starts ~3w
- Gluergic inputs develop
later - increased activity-
dependent synaptic
plasticity during maturation
Functional role of new SGZ neurons
• morphological and electrophysiological maturation (~4-6 weeks)
• spatial memory, explicit learning – responsible for pattern separation
• malfunctioning leads to pathological brain functions (can be a cause and a
consequence, as well):
- epilepsy
- depression, anxiety
- stress
• new neurons: activation of local
interneurons -> strong inhibition at
the network level; during
maturation, increased sensitivity to
activity-dependent plasticity
Solid arrows are supported by experimental evidence; dashed arrows are hypothetical. Colors depict symmetric,
asymmetric, or direct transformation. IPC, intermediate progenitor cell; MA, mantle; MZ, marginal zone; NE,
neuroepithelium; nIPC, neurogenic progenitor cell; oIPC, oligodendrocytic progenitor cell; RG, radial glia; SVZ,
subventricular zone; VZ, ventricular zone.
Neurogenesis within the CNS
Essay questions Describe the cellular composition of the ventricular zone (VZ)! Explain the
functional importance of VZ cells in respect to neurogenesis! / Hogyan épül fel
az embrionális ventrikuláris zóna (VZ)? Milyen sejt(ek) alkotjá(k)? Milyen
szerepet tölt be a VZ az idegrendszer fejlődése során?
What kind of role do radial glial cells play in neurogenesis? Where and when
can they be found within the CNS? What kind of factors regulate their
proliferation and differentiation? / Hol található meg és milyen tulajdonságokkal,
markerekkel jellemezhető a radiális glia? Milyen szerepet tölt be az
idegrendszer fejlődése során? Milyen faktorok irányítják a proliferációjukat,
illetve az elköteleződési lépéseket?
Where does neurogenesis take place in the adult CNS? Give a brief overview
of the newly born neurons! Explain their functional importance! / Hol
keletkeznek új idegsejtek a felnőtt idegrendszerben? Hol és milyen szerepet
töltenek be az újonnan képződő idegsejtek?
Compare the characteristics (similarities and differences) between the steps of
adult neurogenesis within the SVZ and SGZ! / Hasonlítsa össze az SVZ-ben és
az SGZ-ben folyó felnőttkori neurogenezis főbb sajátságait (hasonlóságait és a
különbségeket)!