Review
Patterning the mammalian cerebral cortex

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Abstract

When and how is the area map of the cerebral cortex set up during development? Recent studies indicate that regional pattern emerges early in cortical neurogenesis, and that this pattern does not require cues from extrinsic innervation. Studies of mutant mice indicate a role for embryonic signaling centers and for specific transcription factors in regionalizing the cortex. Thus, it is increasingly probable that the cortex is partitioned using the same types of mechanisms — and in some cases, the same gene families — that are used in patterning other parts of the embryo. This emerging model is likely to be the basis for many future studies. However, new evidence also confirms the special nature of the cerebral cortex, in that cues from developing connections appear to modify and refine the final area map.

Introduction

The mammalian cerebral cortex is a continuous sheet of tissue with an elaborate regional pattern. Its broad divisions are anatomically different types of cortex, such as five-cell-layered neocortex and one-cell-layered archicortex. Within these broad regions, the complex functions of the cortex are distributed among many anatomically distinct areas (Fig. 1). These divisions form a map that is similar from one individual to another and has common topological features across mammalian species. Given the importance of the cortex to mammalian brain function, understanding how this map is established in the developing cortex, and how it is modified between individuals and in different species, could be considered a holy grail in the field of embryonic patterning.

An expectation might be that the cortex is patterned by special mechanisms that are not used elsewhere in the embryo. Thus, a patterning mechanism unique to the brain is emphasized in a classic model of cortical patterning. In this ‘protocortex’ model [1], the sheet of cortical neurons that is initially generated is homogeneous, then patterned into areas relatively late in corticogenesis by cues from axons growing in from the thalamus, a major source of cortical innervation. A contrasting view might be that the cortex is just a particularly complex sheet of epithelium, similar to other epithelia in the embryo, and patterned by similar mechanisms. A version of this idea is encapsulated in a second classic model of cortical patterning [2]. In this ‘protomap’ model, the embryonic cortex is patterned as it is generated. Intrinsic regional differences, presumably specified by molecular determinants, are set up in the ventricular zone (VZ), the progenitor cell layer of the cortex. As newborn neurons leave the VZ and migrate out to form the cortical mantle, they carry an area protomap with them. Innervating axons, when they arrive, could then modify and refine the protomap.

Section snippets

An emerging model of cortical area patterning

Other epithelial sheets, for example, the Drosophila wing imaginal disk, are patterned by signaling centers that release signaling molecules such as WNT, BMP and Hedgehog (HH) proteins, which in turn control the regional expression of specific transcription factors [3], [4]. Thus, a new protomap model of cortical patterning, based on current knowledge of other embryonic systems, might be as follows (Fig. 2).

Signaling molecules released from discrete centers provide early positional information

Patterns of early gene expression reveal that embryonic cortex is not homogeneous

Recently, there has been an explosion in the number of genes reported to be regionally expressed in the developing cortex [6radical dotradical dot]. A few genes are expressed in stable patterns from embryo to adult which therefore act as ‘markers’ of particular area or regional boundaries. These include the gene encoding the limbic system-associated membrane protein (LAMP), a classic marker of limbic cortex [7], [8, and certain genes expressed in the hippocampus [9]. Other gene expression patterns define boundaries

Early cortical regionalization does not depend on thalamic innervation

A clear conclusion is that by gene expression the embryonic cortex, including the VZ, is heterogeneous. How are these regional patterns of gene expression related to the ingrowth of axons from the thalamus or elsewhere? Some patterns evidently precede extrinsic innervation [12], [13, [18, [20], but many do not [9], [11, [13, [18. The earlier specification of some of these patterns was demonstrated in classic studies showing that regional cortical expression of LAMP [7], [21], [22] and latexin,

Signaling centers and local signaling molecules

Evidence for early cortical pattern prompts a search for signaling centers that may initiate the pattern. A prominent feature of the mature area map is that many areas (20 or more in the mouse) are arranged in roughly longitudinal bands along the medial and lateral edges of the cortical sheet (Fig. 1). This organization suggests that signaling centers may lie along the edges of the embryonic cortex, providing positional cues in the medial–lateral axis. Other signaling centers might be

Transcription factor control of cortical pattern

Transcription factors that are regionally expressed in the cortical VZ include Emx2, a vertebrate homolog of the Drosophila head gap gene ems and the LIM-homeodomain (LIM-HD) genes Lhx2 and Lhx5. Emx2 is expressed in a gradient that is high in posteromedial cortex and low anterolaterally ([17], [19; Fig. 2b). Lhx2 expression is strongest in medial cortex, weaker in lateral cortex and not detected in the cortical hem [18radical dot]. Lhx5 is expressed selectively in the medial telencephalon [51radical dot]. Loss of

Late regulation of the cortical area map

Cortical area maps are similar but not identical from one individual to another (Fig. 4c,d). In particular, the relative size of cortical areas can vary greatly. In humans, for example, primary visual cortex, V1, can differ by a factor of three in its surface area. This variation correlates with the size of the visual thalamic relay nucleus, the lateral geniculate nucleus (LGN), but not with total brain mass [62]. How might a size co-variation between thalamus and cortex be achieved? An obvious

Conclusions

Increasingly sophisticated versions of the new protomap model seem likely to direct work in the field of cortical patterning in the near future [2], [11. First, the identity and role of signaling centers in early cortical patterning will need to be explored more fully. Second, links need to be established between early signals and the differential expression of the transcription factors that appear to be involved in cortical patterning. Third, how these and other transcription factors function

Acknowledgements

The authors thank Peter Gruss and Dennis O'Leary for providing preprints of papers discussed in this review. Work in the Grove laboratory was supported by National Institutes of Health (NIH) Grants NS35622 and MH59962 and by a March of Dimes Research Grant. Work in the Ragsdale laboratory was supported by NIH Grant NS35680 and a March of Dimes Basil O'Connor Research Award.

References and recommended reading

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

  • radical dotof special interest

  • radical dotradical dotof outstanding interest

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