Molyneaux BJ, Arlotta P, Macklis JD. 2007. Molecular development of corticospinal motor neuron circuitry. Novartis Foundation symposium. 288:3-15; discussion 15-20, 96-8. Pubmed: 18494249


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.

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Photo of Paola Arlotta

Dr. Arlotta is interested in understanding the molecular laws that govern the birth, differentiation and assembly of the cerebral cortex, the part of the brain that controls how we sense, move and think. She integrates developmental and evolutionary knowledge to investigate therapies for brain repair and for modeling neuropsychiatric disease.

Photo of Jeffrey D. Macklis

Jeffrey Macklis investigates molecular controls and mechanisms over neuron subtype specification, development, diversity, axon guidance-circuit formation, and pathology in the cerebral cortex. His lab seeks to apply developmental controls toward brain and spinal cord regeneration and directed differentiation for in vitro mechanistic modeling using human assembloids.

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