The determination of projection neuron identity in the developing cerebral cortex

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Here we review the mechanisms that determine projection neuron identity during cortical development. Pyramidal neurons in the mammalian cerebral cortex can be classified into two major classes: corticocortical projection neurons, which are concentrated in the upper layers of the cortex, and subcortical projection neurons, which are found in the deep layers. Early progenitor cells in the ventricular zone produce deep layer neurons that express transcription factors including Sox5, Fezf2, and Ctip2, which play important roles in the specification of subcortically projecting axons. Upper layer neurons are produced from progenitors in the subventricular zone, and the expression of Satb2 in these differentiating neurons is required for the formation of axonal projections that connect the two cerebral hemispheres. The Fezf2/Ctip2 and Satb2 pathways appear to be mutually repressive, thus ensuring that individual neurons adopt either a subcortical or callosal projection neuron identity at early times during development. The molecular mechanisms by which Satb2 regulates gene expression involves long-term epigenetic changes in chromatin configuration, which may enable cell fate decisions to be maintained during development.

Introduction

The nervous system is populated by an enormous variety of neurons that show distinct dendritic morphologies, local and long-distance axonal connections, neurotransmitter phenotypes, and patterns of gene expression. The generation of these diverse phenotypes from mitotically active progenitor cells utilizes a range of cellular and molecular strategies. In general, cues derived from the early regionalization of the neural tube act in conjunction with intercellular signals, temporally regulated factors, and cell-intrinsic cues to progressively determine the fates and identities of specific classes of neurons. Recent studies of the developing cerebral cortex have elucidated some of the mechanisms that underlie the production of discrete types of projection neurons. Here we review progress in understanding the strategies by which cortical neurons are assigned layer-specific fates and elaborate their long-distance projections.

Section snippets

The cerebral cortex is organized into layers that are generated sequentially over developmental time

Ever since the time of Cajal, scientists have appreciated that the cerebral cortex is organized in layers that are defined by the densities and morphologies of their constituent neurons. The advent of retrograde tracing techniques and intracellular dye injections revealed that, as a general rule, neurons in the upper layers 2 and 3 tend to form corticocortical connections, including projections to the contralateral hemisphere across the corpus callosum, whereas neurons in layers 5, 6, and the

Cellular studies of cell fate determination suggest a progressive restriction in developmental potential

Transplantation experiments have probed the process by which neurons become committed to the laminar fate that is typical of their time of origin. These studies have demonstrated that by the time a young neuron has progressed through its final mitotic division and is ready to initiate migration, the cell has acquired the information needed to migrate to the layer typical of its birthday, even in an environment in which host neurons are destined for other layers [7, 8, 9]. However, at earlier

Fezf2 and Ctip2 define the fates of subcortical projection neurons

VZ cells at early stages of cortical neurogenesis express a number of transcription factor genes that have the potential to determine or influence the fates of their daughter cells. Some of these (e.g. Otx1) show a clear correlation in expression between early progenitors and deep layer neurons, but have no obvious functional role in the establishment of neuronal fates or identities [13, 29]. However, others do appear to play important roles in fate determination. For example, the zinc-finger

A role for Sox5 in the specification of distinct subtypes of deep layer neurons

Although substantial progress has been made in unravelling the genetic and molecular pathways that control deep layer neuronal identity, little is yet known about the pathways that act upstream of Fezf2 and Ctip2. Recently, however, the SRY-box gene Sox5 has been implicated in regulating the timing of deep layer differentiation [40••]. Sox5 is normally expressed by subcortically projecting neurons in layers 5, 6, and the subplate, and its expression are largely excluded from callosal projection

Mechanisms that direct upper layer neuronal identity

Although our understanding of the mechanisms that produce distinct subtypes of subcortical projection neurons in the deep layers is growing, much less is known about how the brain produces the classes of neurons that populate the upper layers. As with VZ cells and their deep layer progeny, gene expression patterns in the SVZ are correlated with those of neurons in layers 2–4. However, the functional roles of these genes remain poorly understood. For example, the T-box gene Tbr2 is expressed

Satb2 and the determination of callosal projection neuron identity

Neurons that extend axons across the corpus callosum to the opposite cerebral hemisphere are a subtype of neurons that form corticocortical connections. Callosal projection neurons are particularly prominent in the upper layers, although they are present in the deep layers. Recent work has revealed that callosal projection neurons require the chromatin remodeling protein Satb2 for the formation of their normal projections, and that in the absence of Satb2, these cells extend axons toward

Conclusions

Collectively, the studies of the roles of Sox5, Fezf2, Ctip2, and Satb2 during cortical development suggest that an elegant genetic mechanism exists to control the identity of a subcortical versus callosal projection neuron (Figure 2). Early in development, when deep layer neurons are generated, Fezf2 expression in VZ cells may promote the expression of Ctip2 in young neurons, and together these genes confer a subcortical projection neuron fate during differentiation. Differences in the levels

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work is supported by NIH grant EY08411 (National Eye Institute).

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