Ontogenesis in the CNS – neurogenesis during embryonic

development

Formation of the neural tube

neural groove

neural groove neural plate

neural crest

notochord neural tube

The developing neuroepithelium

ventricular zone

(pseudostratified

epithelium)

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

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

Morphogenes influencing cortical neurogenesis

Morphogenes influencing cortical neurogenesis

Environmental clues influencing cortical neurogenesis

Adult neurogenesis

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

BrdU+ cells

Neurogenesis within the adult brain

Neurogenesis within the adult brain

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

Adult neural stem cells within the SVZ

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

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)

Neurogenesis within the adult SVZ

Neurogenesis within the adult SVZ

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 (?)

Adult neural stem cells within the SGZ

Integration on newly born SGZ neurons

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

Integration on newly born SGZ neurons

Neurogenesis within the adult SGZ

Neurogenesis within the adult SGZ

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

Glial-neuronal transition during

adult neurogenesis

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

Neurogenesis within the CNS

Lineage tree of neural stem cells

Lineage tree of neural stem cells

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)!

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