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