Specification of cortical projection neurons: transcriptional mechanisms

The mammalian neocortex is most evolutionarily advanced region of the brain, responsible for sensory perception, integrative-associative function, voluntary motor control, and high-level cognition; it has undergone dramatic expansion during evolution. This capacity for high-order processing emerges from a complex, yet highly organized, six-layered sheet-like structure divided into functionally and cytoarchitectonically distinct areas that contain many distinct neuronal subtypes with function-specific molecular, connectivity and physiological properties. Here, the development and organization of the neocortex are reviewed in the context of recent results revealing functions of individual and combinatorial sets of genes in controlling specification, development, connectivity, and areal function-specific diversity of distinct projection neuron subtypes. First, we describe the diversity of progenitors that give rise to the projection neurons of the neocortex, and discuss current knowledge regarding molecular-genetic programs that regulate progenitor specification, lineage potential, and plasticity. Next, we focus on two distinct, broad projection neuron classes, corticofugal (cortical output) projection neurons and callosal projection neurons (the dominant inter-hemispheric neurons in placental mammals). We describe recent advances in understanding the interplay of combinatorial and sequential molecular-genetic controls over the precise generation and diversity of these developmentally and clinically important neuronal subtypes. Then, we review some possibilities for applying the expanding knowledge of developmental biology of neocortical subtype-specific differentiation toward directed differentiation of human pluripotent stem cells and cellular repair strategies. Finally, we briefly discuss an emerging field regarding implementation of circuit-specific axonal connectivity, circuit formation, and function by subtype-specific subcellular domains, in particular growth cones.