Area and layer patterning in the developing cerebral cortex
Introduction
Landmark studies [1, 2] suggested that a single cortical progenitor cell generates neurons for several layers of the neocortex. Timed environmental cues function in series on the progenitor cell, just before cell division, promoting particular layer fates [1]. Furthermore, cortical progenitors can initially generate neurons for any layer, but as development continues, progenitor potential narrows [2]. These key studies were followed by a period in which layer specification received less attention. Now, several new papers place this topic once again in the spotlight.
Recent findings support a classic model of area specification, in which a ‘protomap’ forms in the neocortical primordium [3]. In this model, cues that specify particular areas act on cortical progenitor cells. A current proposal is that the same families of signaling molecules that pattern other parts of the embryo also establish the spatial coordinates of the protomap. Thus, a source of fibroblast growth factor (Fgf) proteins near the anterior pole of the cortical primordium sets up the anterior–posterior (A–P) axis [4, 5]. Bone morphogenetic proteins (BMPs) and Wingless-Int (Wnt) proteins from the dorsomedial cortical primordium are proposed to regulate the dorsal–ventral (D–V) axis [6, 7, 8, 9]. Several transcription factors, including Emx2, Pax6 and COUP-TF1/Nr2f1 are candidate mediators of map formation [10, 11, 12]. New research clarifies the functions of these patterning molecules, their regulatory interactions, and finally, downstream mechanisms that determine cortical connectivity and function. Here, we review a selection of recent reports on cortical layer and area patterning in mice, monkeys and humans.
Section snippets
Cortical neurogenesis
If areas and layers are specified as cortical neurons are generated [1, 3], then understanding the events and mechanisms of cortical neurogenesis is crucial. In the past few years our knowledge of these events and mechanisms has increased dramatically. Cell division and migration has been followed in real time in cortical slices using confocal time-lapse microscopy and fluorescent labeling of progenitors and their daughter cells. This approach has revealed that radial glial cells, previously
Layer specification
‘Temporal identity’ models of cell fate specification, based on observations of Drosophila neuroblasts [28, 29•], are helpful in considering cortical layer fate. In such models, daughter cell fate is determined by timed extrinsic signals, or by intrinsic changes in the dividing cell that are dependent on successive cell cycles. In Drosophila both models apply, each at a different stage of neuroblast production [28, 29•]. Studies of layer fate in ferret and mouse cerebral cortex also provide
Area patterning
Several gene expression patterns that mark layers in the cortical plate also mark prospective area boundaries. By birth, the expression of genes encoding different classic cadherins clearly demarcates frontal, parietal and occipital domains; expression of other genes marks the transition between primary motor and somatosensory cortex [38]. Area identity is initiated, however, at a much earlier stage [3, 39, 44•, 45, 46]. A recent study, for example, provides evidence that characteristic
Layers and areas
Areas were first identified by cytoarchitecture, including layer organization [63, 64]; conversely, layers differ by area. Indeed, layers have an ‘active’ area identity, as indicated by the ability of layer IV in S1 to guide thalamic axons to their target [48•]. Areas are, therefore, built up of layers, the molecular specifications of which we are beginning to understand. For example, corticospinal projections initially arise from a large part of the neocortex, but are pruned back to become
Human brain pattern
Studying specific brain abnormalities and gene mutations in the human population can reap large rewards in identifying mechanisms of neuronal migration [67••]. The same powerful approach has now been directed towards the development of regional pattern. Polymicrogyria, a small thin cortex with too many convolutions, can appear bilaterally in one or two of the major lobes of the cortex. Findings from a large and geographically varied patient population strongly implicate mutations in an orphan G
Conclusions
New research is rapidly identifying the molecular mechanisms that underlie generation and specification of cortical cell-types [71•], layers and areas. On a larger scale, optical imaging can now bridge molecular and functional studies to reveal the effects of genetic manipulations on the functional topography of the area map. Finally, the power of human genetics, in the hands of experienced neurobiologists, should continue to provide flashes of insight.
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
Acknowledgements
Work in the Grove laboratory was supported by National Institutes of Health grants R01 MH059962 and HD42330, and by a March of Dimes Research Grant.
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