Transcriptional Controls over Neocortical Projection Neuron Identity and Connectivity

Abstract

The complex and sophisticated circuitry of the neocortex is assembled from an extraordinarily diverse repertoire of neuronal subtypes that reside in distinct functional areas. In recent years, a number of key regulators over neocortical projection neuron subtype and area specification have been identified. It is becoming increasingly clear that these regulators function within a highly-interconnected network, acting in parallel, synergistically, and cross-repressively to orchestrate cortical development. Moreover, an emerging understanding of cortical development has revealed that subtype and area identity are intimately interrelated, and that specification occurs based on several sequential molecular decision points. Although great strides have been made in recent years toward understanding molecular controls over neocortical projection neuron development, many important controls remain to be discovered, and mechanisms by which recently-identified regulators act to delineate subtype and area identity are not well understood. In this dissertation, I characterize functions of two zinc finger transcription factors, Ctip2 and Ctip1, in postmitotic projection neuron subtype and area identity acquisition, using in vivo gain- and loss-of-function approaches in the mouse. I find that Ctip2, known for several years as a central functional control over corticospinal motor neuron (CSMN) terminal differentiation and connectivity, is required both cell-autonomously (within CSMN) and non-cell-autonomously (within striatal medium-sized spiny neurons that surround CSMN axons traveling in the internal capsule) for CSMN to achieve proper connectivity with the spinal cord. In addition, I find that Ctip1, a transcription factor not previously functionally investigated in neocortical development, is a novel control over 1) corticothalamic and callosal projection neuron development and projection neuron migration; and 2) postmitotic area identity acquisition and the formation of sensory maps. Taken together, these results reveal previously unknown functions of Ctip1 in neocortical development, and novel sites of action for Ctip2 control over CSMN connectivity. Ctip1 and Ctip2 are transcriptional controls over the postmitotic specification of neocortical projection neuron subtype and area identity, and over projection neuron connectivity with distant targets.