Transcriptional co-regulation of neuronal migration and laminar identity in the neocortex

Abstract

The cerebral neocortex is segregated into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection (pyramidal) neurons and inhibitory interneurons. Development of the neocortex requires the orchestrated execution of a series of crucial processes, including the migration of young neurons into appropriate positions within the nascent neocortex, and the acquisition of layer-specific neuronal identities and axonal projections. Here, we discuss emerging evidence supporting the notion that the migration and final laminar positioning of cortical neurons are also co-regulated by cell type-and layerspecific transcription factors that play concomitant roles in determining the molecular identity and axonal connectivity of these neurons. These transcriptional programs thus provide direct links between the mechanisms controlling the laminar position and identity of cortical neurons. Key words: Neuronal specification, Neuronal migration, Neuronal identity, Axon pathfinding, Pyramidal neuron, Neuronal circuits, Cerebral cortex IntroductionThe cerebral cortex, an extensive sheet of neural tissue at the most superficial part of the cerebral hemispheres, is involved in a variety of higher cognitive, emotional, sensory and motor functions. The emergence of a six-layered neocortex, the phylogenetically most recent part of the cerebral cortex, and its extensive projections to subcortical regions are key features of mammalian evolution. The ability of the neocortex to mediate complex cognitive and motor tasks depends on the accurate execution of molecular processes that control the identity and positioning of neurons and the formation of their precise synaptic connections during development. The incorrect formation of neocortical organization and circuitry might lead to cognitive impairments and increased susceptibility to major psychiatric and neurological disorders (Valiente and Marín, 2010;Liu, 2011;Manzini and Walsh, 2011;Rubenstein, 2011).The neocortex is composed of six horizontal layers (L1-L6; see Glossary, Box 1) that are cytoarchitectonically and functionally distinct. Each layer contains a unique subset of neurons ( Fig. 1), including glutamatergic excitatory projection (pyramidal) neurons (see Glossary, Box 1) and GABAergic inhibitory interneurons (see Glossary, Box 1) (Jones, 1986;DeFelipe and Farinas, 1992). Furthermore, the projection neurons of L2-L6 exhibit marked layerand subtype-specific differences in their molecular expression and axon projections (DeFelipe and Farinas, 1992;O'Leary and Koester, 1993;Molyneaux et al., 2007). For example, corticofugal axons targeting subcortical structures arise solely from deep-layer (L5 and L6) and subplate (SP; see Glossary, Box 1) neurons, whereas upper-layer (L2-L4) neurons project within the cortex, either intra-hemispherically or contralaterally, mostly via the corpus callosum (see Glossary, Box 1). In addition to projection neurons, interneurons of distinct lineages and morphological, neurochemical and electro...

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