Review
Molecular mechanisms underlying cell fate specification in the developing telencephalon

https://doi.org/10.1016/S0959-4388(02)00286-6Get rights and content

Abstract

The cellular properties of neural progenitor cells have been best characterized in the telencephalon, the most complex region of the vertebrate brain. In recent years, several transcription factors, including Mash1, Ngn1/2, Pax6 and Emx1/2, and signaling molecules, such as Notch and bone morphogenetic proteins, have emerged as important players in key areas of telencephalic development. These include the specification of positional identity, the proliferation of neural stem cells and their commitment to a neuronal or glial fate, and the differentiation of layer-specific neuronal phenotypes in the cerebral cortex.

Introduction

The embryonic telencephalon gives rise to a diverse array of neuronal and glial cells that undergo intricate patterns of cell migration to reach their final positions in the mature cerebral cortex and basal ganglia. Classically, the embryonic telencephalon has been subdivided into a dorsal pallium and a ventral subpallium, which give rise to the mammalian cerebral cortex and basal ganglia (striatum and pallidum), respectively. The dorsal telencephalon can be further subdivided into: the medial pallium (MP), which gives rise to the archicortex, including the hippocampus; the dorsal pallium (DP), which is the anlage of the neocortex; the lateral pallium (LP), which generates the olfactory cortex; and the ventral pallium (VP), from which the claustroamygdaloid complex is generated. Each of these pallial domains gives rise to a distinct region of the adult brain 1., 2••. (Fig. 1). Similarly, the ventral telencephalon consists of two distinct progenitor domains, the lateral (LGE) and medial (MGE) ganglionic eminences, generating the striatum and pallidum, respectively [1]. Although these telencephalic subdivisions were initially delineated on the basis of differences in morphology, connectivity and neurochemical profiles, dorsal and ventral domains of the telencephalon are also distinguished embryonically by distinct patterns of gene expression, reflecting the initial acquisition of regional identity by progenitor populations (Fig. 1).

Composite analyses of gene expression patterns have allowed a further refinement of the identity and positions of unique embryonic subcompartments within the telencephalon. Recent progress has also been made regarding the manner in which these domains are initially established. Similar to more caudal regions of the nervous system, extracellular signals involved in the initial patterning of the telencephalic neuroepithelium include sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), nodal and retinoids [3•]. Subsequently, telencephalic regional identities are maintained through cross-regulatory interactions involving homeodomain and basic helix–loop–helix (bHLH) transcription factors. These genetic interactions similarly underly the maintenance of progenitor domains in the caudal neural tube [4]. Here, we address the issue of how regionally specified progenitors acquire their identities and subsequently differentiate into cell types specific to their location, focusing on the role of intrinsic events and extrinsic signals in the specification of neuronal and glial cell types.

Section snippets

Specification of regional identity in the telencephalon

What is the significance of the division of the embryonic telencephalon into molecularly distinct progenitor domains? Genetic analyses have revealed that regional ly restricted genes participate in the specification of the identity of the telencephalic territory in which they are expressed. For instance, the Lhx2 LIM-homeodomain transcription factor operates in the cortical anlage to repress the spread of the cortical hem, the most medial part of the dorsal telencephalic neuroepithelium that is

Molecular regulation of neuronal versus glial cell fate choice in the telencephalon

One of the first decisions that neural progenitors must make during development is whether to adopt a neuronal or a glial cell fate. In the telencephalon, as in other regions of the neural tube, neural stem cells (NSCs) alter their output over time. They initially give rise to committed neuronal precursors and only later to glial precursors 21••., 22., although recent lineage mapping data suggests an early commitment of some cortical progenitors to glial fates [23].

The role of Notch signaling

Notch signaling has recently been shown to influence this switch in the peripheral nervous systems (PNS), acting instructively in neural crest stem cells to promote a heritable and irreversible switch to gliogenesis [24]. Similarly, activation of the Notch pathway drives Müller glia formation in the retina [25]. Consistent with these studies, Tanigaki et al. [26] have shown that Notch activation in multipotent progenitors from the adult hippocampus promotes an accelerated and irreversible

Gliogenic signals

Several extracellular factors, including leukemia inhibitory factor (LIF), BMP2 and fibroblast growth factor 2 (FGF2), influence glial fate decisions in an instructive fashion in the telencephalon 36., 37•. (Fig. 2). Recently, some of the downstream effectors of these signaling molecules have been shown to have dual functions: participating both in the activation of gliogenic differentiation pathways and simultaneously inhibiting neurogenic differentiation (Fig. 3). For instance, BMP2 and its

Proneural proteins in neuronal cell fate

Consistent with the idea that the proneural bHLH proteins are intrinsic mediators of the neuronal versus glial fate decision, loss-of-function studies have demonstrated that both Mash1 and Ngn2 promote the specification of a neuronal over a glial fate in the embryonic telencephalon [40••]. Mash1, Math3 and NeuroD have been shown to have similar activities in the midbrain, hindbrain and retina 41., 42•.. Furthermore, in gain-of-function experiments in vitro, NeuroD, Mash1 and Ngns can drive

Oligodendrocyte fate specification

NSCs also have an oligodendrocyte potential, although it appears to be only expressed in vivo in defined ventral positions of the embryonic neural tube. Through the use of quail chick chimeras, the anterior entopeduncular area (AEP) has been identified as the site of origin of oligodendrocyte precursors (OLPs) in the embryonic telencephalon [47]. OLPs, which express platelet-derived growth factor receptor α (PDGFRα), are born in the AEP and later migrate tangentially to populate the MGE, LGE

Specification of neuronal phenotypes in the ventral telencephalon

The subdivision of the telencephalic ventricular zone by the regionalized expression of transcription factors is followed by the differentiation of distinct types of neurons in each of these subdivisions [3•]. In the basal telencephalon, differentiating neurons are primarily γ-amino butyric acid (GABA)ergic and are characterized by expression of the homeodomain proteins Dlx5 and Dlx6 1., 3•., and by Nkx2.1, Lhx6 and Lhx7 expression for neurons born in the MGE 57., 58.. GABAergic interneurons

Neuronal specification in the cerebral cortex

The cerebral cortex is a six layered structure comprised primarily of glutamatergic projection neurons, originating from dorsal telencephalic progenitors, and of interneurons of ventral origin. Cortical projection neurons are distinguished early on by their expression of Tbr1 and several bHLH proteins including NeuroD, NeuroD2, Math2 and Math3 11., 69.. It has been proposed that bHLH transcription factors acting in regulatory cascades orchestrate neuronal differentiation 70., 71.. Consistent

Conclusions

A great deal of progress has been made in our understanding of the initial patterning events and early cell fate decisions in the telencephalon. However, we are still a long way from understanding how the multitude of different neuronal and glial cell types generated in this region of the brain acquire their specific phenotypes. What is becoming clear is that each step in the specification of a defined cell fate involves not a single transcription factor but the combinatorial actions of several

Update

A recent paper from the laboratory of Chris Walsh [86•] provides evidence that BMP signals produced by the cortical hem induce pallial expression of Lhx2 via a complex, bimodal mechanism. This work provides new insights into the genetic pathways underlying cortical development and highlights the importance of the cortical hem as a cortical organizing center. Another recent publication [87•] provides evidence that GABAergic neurons and oligodendrocytes in the dorsal telencephalon originate from

Acknowledgements

We would like to thank Siew-Lan Ang, Kenny Campbell, Magdalena Götz, Uwe Strähle and colleagues from F Guillemot’s laboratory for their insightful comments on the manuscript. We would also like to thank Kenny Campbell, Gord Fishell, Magdalena Götz and John Rubenstein for communicating unpublished data and manuscripts in press.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (87)

  • E. Hartfuss et al.

    Characterization of CNS precursor subtypes and radial glia

    Dev Biol

    (2001)
  • D. Henrique et al.

    Maintenance of neuroepithelial progenitor cells by Delta-Notch signalling in the embryonic chick retina

    Curr Biol

    (1997)
  • D.J. Solecki et al.

    Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation

    Neuron

    (2001)
  • T. Ohtsuka et al.

    Roles of the bHLH genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain

    J Biol Chem

    (2001)
  • Y. Sun et al.

    Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms

    Cell

    (2001)
  • M. Nieto et al.

    Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors

    Neuron

    (2001)
  • D.J. Anderson

    Stem cells and pattern formation in the nervous system the possible versus the actual

    Neuron

    (2001)
  • Q. Zhou et al.

    Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors

    Neuron

    (2000)
  • Q.R. Lu et al.

    Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system

    Neuron

    (2000)
  • Q. Zhou et al.

    The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2

    Neuron

    (2001)
  • S. Wang et al.

    A role for the helixloophelix protein Id2 in the control of oligodendrocyte development

    Neuron

    (2001)
  • S.A. Anderson et al.

    Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons

    Neuron

    (1997)
  • J.E. Lee

    Basic helix-loop-helix genes in neural development

    Curr Opin Neurobiol

    (1997)
  • R. Kageyama et al.

    bHLH transcription factors and mammalian neuronal differentiation

    Int J Biochem Cell Biol

    (1997)
  • R. Mizuguchi et al.

    Combinatorial roles of Olig2 and Neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons

    Neuron

    (2001)
  • J.M. Weimann et al.

    Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets

    Neuron

    (1999)
  • R.F. Hevner et al.

    Tbr1 regulates differentiation of the preplate and layer 6

    Neuron

    (2001)
  • C. Zhou et al.

    The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons

    Neuron

    (1999)
  • E.S. Monuki et al.

    Patterning of the dorsal telencephalon and cerebral cortex by a roof plate-Lhx2 pathway

    Neuron

    (2001)
  • L. Puelles et al.

    Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx2.1, Pax6, and Tbr-1

    J Comp Neurol

    (2000)
  • K. Yun et al.

    Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon

    Development

    (2001)
  • E.A. Grove et al.

    The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice

    Development

    (1998)
  • S.M.K. Lee et al.

    A local Wnt-3a signal is required for development of the mammalian hippocampus

    Development

    (2000)
  • J. Galceran et al.

    Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1

    Development

    (2000)
  • A. Stoykova et al.

    Pax6 modulates the dorsoventral patterning of the mammalian telencephalon

    J Neurosci

    (2000)
  • H. Toresson et al.

    Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2

    Development

    (2000)
  • C. Fode et al.

    A role for neural determination genes in specifying the dorso-ventral identity of telencephalic neurons

    Genes Dev

    (2000)
  • M. Yoshida et al.

    Emx1 and Emx2 functions in development of dorsal telencephalon

    Development

    (1997)
  • S. Tole et al.

    Emx2 is required for growth of the hippocampus but not for hippocampal field specification

    J Neurosci

    (2000)
  • A. Mallamaci et al.

    Area identity shifts in the early cerebral cortex of Emx2/ mutant mice

    Nat Neurosci

    (2000)
  • T. Theil et al.

    Gli3 is required for Emx gene expression during dorsal telencephalon development

    Development

    (1999)
  • L. Sussel et al.

    Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum

    Development

    (1999)
  • J.G. Corbin et al.

    The Gsh2 homeodomain gene controls multiple aspects of telencephalic development

    Development

    (2000)
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