Review
Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex

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Abstract

The adult mammalian neocortex, the major region of the cerebral cortex, is divided into functionally specialized areas, defined by distinct architecture and axonal connections. Extrinsic influences, such as thalamocortical input, and genetic regulation, intrinsic to the dorsal telencephalon, control the gradual emergence of area-specific properties during development. Major recent advances in this field include: the first demonstration of the genetic regulation of arealization, implicating the transcription factors Emx2 and Pax6 in the direct control of area identities; and the demonstration of the potential role of the signaling protein, fibroblast growth factor 8, in the early patterning of arealization genes, such as Emx2.

Introduction

The neocortex, a dorsal telencephalic structure unique to mammals, is the largest region of the cerebral cortex and the one that exhibits the most substantial phylogenetic expansion and specialization 1., 2.. The neocortex is also the most highly differentiated region of the cerebral cortex, having six major layers in its radial dimension. In its tangential dimension, the neocortex, like other cortical regions, is organized into subdivisions referred to as areas (Fig. 1a). Areas are distinguished from one another by major differences in their cytoarchitecture and chemoarchitecture, and their input and output connections. The unique architecture and connections specific for each area determine, in large part, the functional specializations that characterize areas in the adult. In the adult, the transition from one neocortical area to another is not graded, but is often abrupt with sharp borders.

It has been assumed that the specification and differentiation of neocortical areas is controlled by interplays between genetic — intrinsic — and epigenetic — extrinsic — mechanisms 3., 4., 5., but, until recently, most experimental evidence has implicated extrinsic mechanisms, in particular the influence of thalamocortical axons (TCAs) [6]. Only in the last two years has compelling evidence for the genetic regulation of arealization begun to emerge, including the first demonstration of regulatory genes that control area specification 7••., 8••. and evidence for patterning centers and signaling molecules that may set up the initial patterning of these genes [9••]. These and other important advances have spawned numerous review articles on topics of cortical development 10., 11., 12., 13., 14.. Here, we provide an update and synthesis of this dynamic field.

Section snippets

Corticogenesis

During development, the areas of the neocortex differentiate within an earlier, more uniform structure, comprised of postmitotic neurons and termed the cortical plate (CP) (Fig. 1b,c). Most neocortical neurons, including all projection neurons, are generated within the ventricular zone (VZ) of the dorsal aspect of the lateral ventricle. The first postmitotic neurons accumulate on the top of the VZ, forming the preplate (PP), positioned just beneath the pial surface. Neurons subsequently

Differentiation of areas

The CP lacks the many features that distinguish areas in the adult, even after all the neurons have been generated and layers begin to differentiate within it. The sharp architectural borders clearly evident between many areas in the adult are lacking in the CP; instead the architecture of the CP is uniform across its tangential extent. Also absent are the restricted, area-specific distributions of distinct types of projection neurons, characteristic of the functional specializations of

Role of thalamocortical axon projections in arealization

TCAs originating in the principal sensory nuclei of the dorsal thalamus form the major input to the neocortex and relay visual, auditory and somatic sensations to the primary sensory areas of the neocortex, in an area-specific manner. Because TCAs are the sole source of modality-specific sensory information to the neocortex, clearly, the functional specializations of the primary sensory areas are defined by, and dependent upon, TCA input. Numerous studies have shown that the differentiation of

Molecular control of area-specific thalamocortical projections

Although considerable recent progress has defined the molecular control of TCA pathfinding from the dorsal thalamus to the neocortex 27., 28., 29., 30., 31., 32., a similar characterization of the area-specific targeting of TCAs within the neocortex has lagged behind. As in the retinotectal system [33], area-specific TCA targeting is likely primarily controlled by guidance molecules, but it can also be influenced by neural activity, because blockade of neural activity results in aberrant areal

Barrels

S1 of rodents is characterized by unique functional modules, termed barrels, comprised of layer 4 neurons aggregated around dense clusters of arborizations of TCAs that arise from the VP. Barrel patterns mirror the distribution of large whiskers on the snout; this pattern is reiterated in specific brainstem nuclei and in the VP, where ‘barreloids’ correspond to barrels (Fig. 2). The differentiation of barrels depends upon intact connections with the periphery [45]. Heterotopic transplantations

Differential gene expression intrinsic to the neocortex

Evidence for the genetic control of arealization has only been obtained in the past few years. Initially, this evidence was indirect and limited to descriptions of genes—including those encoding transcription factors and nuclear receptors, cell adhesion molecules, and axon guidance receptors and ligands—expressed in graded or restricted patterns within the VZ or CP prior to TCAs entering the neocortex 43., 53., 54., 55., 56.. The proposal that these differential patterns of gene expression are

Genetic regulation of area identity

Genes that regulate arealization presumably confer area identities to cortical cells and regulate the expression of axon guidance molecules that control the area-specific targeting of TCAs. Two genes proposed to regulate arealization are the homeodomain transcription factor Emx2 and the paired-box transcription factor Pax6 [3]. Emx2 is expressed in a low rostrolateral to high caudo-medial gradient [65] and Pax6 in a high rostrolateral to low caudomedial gradient [66] across the VZ of the

Signaling molecules that may initiate cortical patterning

Recent studies have begun to define candidate patterning centers and their signaling molecules that act early in development to establish and maintain the graded expression of regulatory genes across the neocortical VZ 7••., 73., 74. (Fig. 5). Several secreted proteins, including fibroblast growth factor (FGF) 8, Sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), and Wnts, cooperate to establish other developmental fields, such as the limb buds 75., 76.. FGF8 is produced in the anterior

Genetic fingerprinting of areas

How is the graded expression of regulatory genes, such as Emx2 and Pax6, translated into downstream gene expression patterns with abrupt borders that relate to areas? Studies in Drosophila embryos have defined distinct mechanisms whereby transcription factors regulate the sharply bordered expression of downstream genes (Fig. 6). For example, the graded distribution of a single regulatory protein, Dorsal, generates, through concentration-dependent differences in binding efficacy to gene promoter

Conclusions

Major advances have been made in the past two years towards understanding the mechanisms that control the arealization of the neocortex. These advances include the first direct demonstration of the genetic regulation of arealization, which implicate roles for the transcription factors Emx2 and Pax6, and the signaling molecule, FGF8. To date, this evidence is largely limited to alterations in patterns of gene expression and area-specific TCA projections in neonatal mice. Thus, it will be

Acknowledgements

Work in the authors’ laboratory is supported by National Institutes of Health grant NS31558 (DDM O’Leary). We thank K Bishop and N Dwyer for helpful discussions.

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 (99)

  • D.D.M. O'Leary et al.

    Molecular development of sensory maps: representing sights and smells in the brain

    Cell

    (1999)
  • S.C. Suzuki et al.

    Neuronal circuits are subdivided by differential expression of type-II classic cadherins in postnatal mouse brains

    Mol Cell Neurosci

    (1997)
  • D.D.M. O'Leary et al.

    Eph receptors and ephrins in neural development

    Curr Opin Neurobiol

    (1999)
  • N. Sestan et al.

    Independent parcellation of the embryonic visual cortex and thalamus revealed by combinatorial Eph/ephrin gene expression

    Curr Biol

    (2001)
  • R.S. Erzurumlu et al.

    Neural activity: sculptor of ‘barrels’ in the neocortex

    Trends Neurosci

    (2001)
  • K. Sharma et al.

    LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons

    Cell

    (1998)
  • T. Tsuchida et al.

    Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes

    Cell

    (1994)
  • C. Zhou et al.

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

    Neuron

    (1999)
  • A.T. Dudley et al.

    Constructive antagonism in limb development

    Curr Opin Genet Dev

    (2000)
  • P.H. Crossley et al.

    Coordinate expression of FGF8, Otx2, BMP4, and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles

    Neuroscience

    (2001)
  • S. Tole et al.

    Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toesJ

    Dev Biol

    (2000)
  • J. Rusch et al.

    Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryo

    Curr Opin Genet Dev

    (1996)
  • S. Small et al.

    Regulation of two pair-rule stripes by a single enhancer in the Drosophila embryo

    Dev Biol

    (1996)
  • R.G. Northcutt et al.

    The emergence and evolution of mammalian neocortex

    Trends Neurosci

    (1995)
  • L. Krubitzer et al.

    Arealization of the neocortex in mammals: genetic and epigenetic contributions to the phenotype

    Brain Behav Evol

    (2000)
  • D.D.M. O'Leary et al.

    Specification of neocortical areas and thalamocortical connections

    Annu Rev Neurosci

    (1994)
  • P. Rakic

    Specification of cerebral cortical areas

    Science

    (1988)
  • A. Chenn et al.

    Development of the cerebral cortex: machanisms controlling cell fate, laminar and areal patterning, and axonal connectivity

  • K.M. Bishop et al.

    Regulation of area identity in the mammalian neocortex by Emx2 and Pax6

    Science

    (2000)
  • A. Mallamaci et al.

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

    Nat Neurosci

    (2000)
  • T. Fukuchi-Shimogori et al.

    Neocortex patterning by the secreted signaling molecule FGF8

    Science

    (2001)
  • E.S. Monuki et al.

    Mechanisms of cerebral cortical patterning in mice and humans

    Nat Neurosci

    (2001)
  • M. Sur et al.

    Development and plasticity of cortical areas and networks

    Nat Rev Neurosci

    (2001)
  • D.S. Rice et al.

    Role of the reelin signaling pathway in central nervous system development

    Annu Rev Neurosci

    (2001)
  • Z. Molnar

    Development and evolution of thalamocortical interactions

    Eur J Morphol

    (2000)
  • J.G. Corbin et al.

    Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain

    Nat Neurosci

    (2001)
  • O. Marin et al.

    A long, remarkable journey: tangential migration in the telencephalon

    Nat Rev Neurosci

    (2001)
  • O. Marin et al.

    Sorting of striatal and cortical interneurons regulated by semaphorin–neuropilin interactions

    Science

    (2001)
  • F. Polleux et al.

    Pre- and post-mitotic events contribute to the progressive acquisition of area-specific connectional fate in the neocortex

    Cereb Cortex

    (2001)
  • C. Dehay et al.

    Cell-cycle kinetics of neocortical precursors are influenced by embryonic thalamic axons

    J Neurosci

    (2001)
  • J.E. Braisted et al.

    Netrin-1 promotes thalamic axon growth and is required for proper development of the thalamocortical projection

    J Neurosci

    (2000)
  • Bagri A, Marin O, Plump AS, Mak J, Pleasure SJ, Rubenstein JLR, Tessier-Lavigne M: Slit proteins prevent midline...
  • R. Tuttle et al.

    Defects in thalamocortical axon pathfinding correlate with altered cell domains in Mash1-deficient mice

    Development

    (1999)
  • T. Pratt et al.

    A role for Pax6 in the normal development of dorsal thalamus and its cortical connections

    Development

    (2000)
  • H. Kawano et al.

    Pax6 is required for thalamocortical pathway formation in fetal rats

    J Comp Neurol

    (1999)
  • S.M. Catalano et al.

    Activity-dependent cortical target selection by thalamic axons

    Science

    (1998)
  • A. Ghosh et al.

    Requirement for subplate neurons in the formation of thalamocortical connections

    Nature

    (1990)
  • K.J. Huffman et al.

    Formation of cortical fields on a reduced cortical sheet

    JNeurosci

    (1999)
  • K. Korematsu et al.

    Expression of cadherin-8 mRNA in the developing mouse central nervous system

    J Comp Neurol

    (1997)
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