glutamatergic cortical neurogenesis€¦ · ca r nd cf g s h po b 205,1 7( 6):39-4 heinrich c, blum...
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Glutamatergic cortical neurogenesis
148-10/10-PS
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TIME EMBRYONIC BIRTHNeuroepithelialcell● Notch1■ AP2γ■ Emx1■ Emx2■ Hes1■ Hes5■ ki67■ NICD■ P-H3■ Pax6■ Tailless
Early bornyoung neuron▲ βIII tubulin▲ DCX▲ Reelin
Young neuron▲ DCX▲ Lis1▲ Trim32■ Neurog2
Radial glia● ErbB2 ● GLAST● Notch1 ● Notch3▲ aPKC ▲ BLBP▲ Pals1 ▲ Par3▲ Par6 ■ AP2γ■ Emx1 ■ Emx2■ Sox2 ■ Hes1■ Hes5 ■ ki67■ P-H3 ■ Neurog1■ Neurog2 ■ Pax6■ Tailless
Basal progenitor■ Brn1■ Brn2■ Cux1■ Cux2■ Tbr2■ Neurog1■ Neurog2■ phNeurog2
Radial glia (generating astroglia)■ Ring1B■ Olig2
Young neuron▲ βIII tubulin▲ DCX■ Math2■ NeuroD■ phNeurog2■ Tbr1
Radial glia ■ AP2γ
Deep layer neuron■ Ctip2■ Fezf2■ NeuN■ Sox5■ Tbr1
Basal progenitor ■ Cux1■ Cux2■ NeuroD4■ Neurog2■ Tbr2
Upper layer neuron■ Cux1■ Cux2■ Satb2■ NeuN
Astrocyte● GLAST● GLT1▲ GFAP▲ Glutamine synthetase▲ S100β
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To other parts of the cortex
To other parts of the cortex
To other parts of the brain andspinal cord
● Reelin, ■ Lhx5
● PlxnD1, ■ Bhlhb5,■ Brn1, ■ Brn2,■ Cux1, ■ Cux2,■ Lhx2, ■ Mef2c,■ Tle1, ■ Tle3
● PlxnD1, ■ Bhlhb5,■ Brn1, ■ Brn2,■ Cux1, ■ Cux2,■ Lhx2, ■ Lmo3,■ Mef2c, ■ Tle1,■ Tle3
■ Bhlhb5, ■ Brn1,■ Cux1, ■ Cux2,■ Lhx2, ■ Mef2c
● PlxnD1, ● Sema3e,■ Bhlhb5, ■ Brn1,■ Brn2, ■ Clim1,■ Ctip2, ■ Er81,■ Fezf2, ■ FoxO1,■ Lmo4, ■ Otx1,■ Satb2, ■ Sox5,■ Tle4
● Sema3e, ■ Ctip2,■ Fezf2, ■ Foxp2,■ Lmo3, ■ Otx1,■ Sox5, ■ Tle4
ToTofo
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● ●
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■ ■
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ToTofo
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Medial pallium
Dorsal pallium
Lateralpallium
Ventral pallium
Dorsal lateral ganglionic eminence
Cortical hem
Medial ganglionic eminence
Ventral lateral ganglionic eminence
Layered structure of developed neocortexTemporal development of the neocortexProgenitor domains of developing forebrain
Neuroepithelial cell Astrocyte
Young neuron Neurogenic basal progenitor
Radial glial cell Oligodendrocytic basal progenitor
Deep & Upper Stellate neuronlayer neuron
Key
l : Membrane
s : Intracellular
n : Nuclear
Key
At an early stage, the developing neocortex consists of a singlelayered epithelium, called the neuroepithelium. Neuroepithelialcells divide generating both new epithelial cells and some earlyneurons (Cajal-Retzius cells) which settle in the marginal zone. Subsequently, neuroepithelial cells transform into radial glia, aprocess which involves upregulation of glial markers such as
BLBP and GLAST. These radial glial cells self-renew as stemcells and generate the next wave of neurons. By virtue of theirlong radial process towards the pial surface, radial glia alsoserve as a scaffold for the migration of neurons towards thedeveloping cortical plate.At later stages, radial glia begin to give rise to new types of
progenitors, called basal progenitors, thereby creating a newgerminative zone, the so-called subventricular zone. These, inturn, divide generating either neurons or a next generation ofbasal progenitors. Neurons continue to migrate towards the cortical plate wherethey settle in an inside-out fashion, i.e. later born neurons pass
earlier born neurons, thus creating the distinct cortical layers. At late corticogenesis (around birth), radial glia lose theirneurogenic potential and either transform directly into astrocytesor give rise to astrocyte progenitors.Some of the radial glia also generate progenitors foroligodendrocytes or transform into ependymal cells (not depicted).
The dorsal part of the mouse (E 12.5) forebrain(purple area) is the germinative zone for variouskinds of excitatory neurons of the neocortex (usingthe transmitter glutamate) as well as corticalastrocytes and some oligodendrocytes. In contrast, most, if not all, cortical interneurons(inhibitory neurons using the transmitter GABA) arise
from the medial ganglionic eminence (MGE) of theventral forebrain (grey area) from whence theymigrate tangentially into the neocortex. Mutual negative loops of transcription factors definethe boundary between the domains of the dorsal andventral forebrain.
By Benedikt Berningerand Abcam
The developed neocortex consists of six layers(enumerated by Roman numbers). Layer I harbors fewcells and most neurons are located between layers II-VI.Generally, neurons of the deeper layers have beengenerated earlier than those of the upper layers.They differ in morphology, connectivity and theiraxonal projection from each other.Selective expression of transcription factors is
responsible for this specification. Some transcriptionfactors are expressed only during specific phases,while others persist. This allows for the identificationof the distinct subtypes of glutamatergic neuronsbased on their transcription factor expression.Not depicted are a variety of GABAergic interneurons(originating from the ventral telencephalon),responsible for local inhibition.
References:Guillemot F. Cellular and molecular control of neurogenesis in the mammalian telencephalon. Curr Opin Cell Biol. 2005, 17(6):639-47.
Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger B. Directingastroglia from the cerebral cortex into subtype specific functional neurons PLoS Biol. 2010, 8(5):e1000373.
Kriegstein A. and Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 2009,32:149-84.
Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci.2007, 8:427-37.
Pinto L and Götz M. Radial glial cell heterogeneity-the source of diverse progeny in the CNS. Prog Neurobiol. 2007, 83:2-23.
Dr. Benedikt Berninger is a researcher at the Institute of Physiology, LMU München, Germany. He works on the specification ofneural stem cells into specific neuron subtypes as well as the re-specification of parenchymal glia into neurons (reprogramming).
www.abcam.com/cortical-neurogenesis
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