| Corticospinal motor neurons (CSMN), also known as "upper motor neurons," form the basis of voluntary motor control in humans. Located in the cerebral cortex, CSMN extend extremely long axons that synapse on lower motor neurons in the spinal cord. While the anatomical and functional development of this system has been extensively studied, the molecular mechanisms underlying the development of CSMN remain unknown. CSMN degeneration is a key component of motor neuron degenerative diseases such as amyotrophic lateral sclerosis, and their injury contributes to a loss of motor function in spinal cord injury. Strategies to repair CSMN are limited by a lack of understanding of the molecular controls over CSMN development.; In order to elucidate the molecular mechanisms underlying the development of CSMN, I purified CSMN at distinct stages of development in vivo and compared their gene expression to two other pure populations of cortical projection neurons: callosal projection neurons and corticotectal projection neurons. I found genes that are instructive for CSMN development, as well as genes that are excluded from CSMN and are restricted to other populations of neurons, even within the same cortical layer. Functional characterization of the first two of the newly characterized genes demonstrates that they each play critical roles in the development of CSMN.; The first gene, Ctip2, is a critical regulator of CSMN axon extension to the spinal cord. In the absence of Ctip2, CSMN axons exhibit defects in fasciculation, outgrowth, and pathfinding, resulting in the failure of CSMN to connect to the spinal cord. The second gene, Fezl, is required for the specification of corticospinal motor neurons and other subcerebral projection neurons, which are absent from Fezl null-mutant neocortex. Overexpression of Fezl results in excess production of deep layer projection neurons and arrested migration of these neurons in the germinal zone. Therefore, Fezl plays a central role in the specification of corticospinal motor neurons and other subcerebral projection neurons. Together, these data provide new insight into the molecular controls over the development of CSMN and a foundation for future investigations into the basic mechanisms underlying the development of neuronal diversity in the cerebral cortex. |
