Abstract

The organization, function and evolution of the brain depends centrally on the precise development of a wide diversity of distinct neuronal subtypes. Furthermore, given the heterogeneity of neuronal subtypes within the CNS and the complexity of their connections, attempts to functionally repair circuitry will require a detailed understanding of the molecular controls over differentiation, connectivity and survival of specific lineages. Toward these goals, we recently identified developmentally regulated transcriptional programmes for specific lineages of long-distance neocortical projection neurons as they develop in vivo (in particular, for corticospinal motor neurons; CSMN). We purified CSMN, a clinically important population of neocortical projection neurons, at distinct stages of development in vivo, and compared their gene expression to that of two other pure populations of neocortical projection neurons. We identified novel and largely uncharacterized genes that are instructive for CSMN development and implicated in key developmental processes. These include Fezf2 (also known as Fezl), a regulator of subcerebral projection neuron identity, and Ctip2 (also known as Bcl1b), a regulator of the fasciculation, outgrowth and pathfinding of CSMN axonal projections to the spinal cord. Loss-of-function and gain-of-function analysis for multiple identified genes reveal programmes of combinatorial molecular controls over the precise development of key neocortical and other forebrain projection neuron populations that elucidate organization and function of the forebrain, and that might be manipulated toward functional cellular repair of complex brain circuitry.