The corticospinal system is the principal motor pathway for controlling voluntary movements in mammals. This system is formed by long-range descending axonal projections from layer 5 neurons in sensorimotor neocortical areas to terminal targets in the brain stem and spinal cord. As the axons from cortex descend into the spinal cord, they also form collateral connections with intermediate targets involved in sensorimotor integration, such as the striatum and thalamus. How corticospinal neurons differentiate, navigate their axons and what is the importance of synaptic contacts with the intermediate subcortical targets is still poorly understood. We and others have recently shown that the transcription factor fez family zinc finger 2 (FEZF2;also known as FEZL or ZFP312) is required for the formation of corticospinal axonal projections, dendritic arborization, and the expression of multiple genes previously implicated in the development of neuronal circuits for sensorimotor integration. However, FEZF2 downstream signaling effectors are still unknown. In my preliminary studies, I have found that FEZF2-mediated transcriptional activation of two axon guidance molecules, is required for the formation of the corticospinal tract and its thalamic collaterals. In addition, my preliminary observations indicate that regionally restricted expression is not only transcriptionally regulated by FEZF2, but suggest that it depends on the formation of subcortical projections. Here, I propose to directly test the central hypothesis of this proposal: that retrograde signaling controls gene expression and differentiation of layer 5 neurons constituting the corticospinal system. Results should have a significant impact on the understanding of sensorimotor integration and treatment approaches for spinal cord injury and the regeneration of severed corticospinal tract axons in adulthood.
