The long-term goals of the proposed experiments are both to elucidate the neuron subtype-specific development of neocortical projection neuron circuitry and to repair diseased neocortical projection neurons. During the development of the mammalian telencephalon, spatially and temporally heterogeneous progenitor cells generate a rich variety of projection neuron subtypes. Although key molecular controls over regionalization of progenitors have been extensively characterized, the investigation of genes regulating projection neuron subtype identity acquisition in postmitotic neurons has only relatively recently begun. Recent work in the Macklis laboratory (Arietta et al., Neuron '05; Molyneaux et al., Neuron '05; Ozdinler and Macklis, Nature Neurosci. '06; Molyneaux et al.. Nature Rev. Neurosci. '07; Arietta et al., J. Neurosci., '08; Lai et al.. Neuron '08; Joshi et al., Neuron '08; Azim et al., '09, Srubeck Tomassy et al., '09), complemented and broadened by work from other investigators, has identified a combinatorial program of transcription factor controls over the specification and differentiation of cortical projection neurons from progenitor cells. One such transcription factor, COUP-TF interacting protein 2 (Ctip2) has been shown by our laboratory to be centrally important for the differentiation of both corticospinal motor neurons (CSMN) (and related subcerebral projection neurons) in the neocortex and medium-sized spiny neurons (MSN) in the striatum; however, the specific molecular differentiation programs executed by Ctip2 in these important neuron types is unknown. In this proposal, I outline a program of research designed to investigate the functions of Ctip2 in CSMN development. I propose to 1) identify the specific role(s) of Ctip2 in CSMN axon extension and fasciculation; 2) delineate the specific role(s) of Ctip2 in CSMN axon pathfinding; and 3) investigate a possible interaction between Ctip2 and its family member Ctipl in the developing cortex. These studies will elucidate the mechanisms by which Ctip2, a central regulator of CSMN identity, acts alone and in concert with other genes to instruct the development of this clinically important neuron type. The proposed research has significant clinical implications. As CSMN are the brain neurons that degenerate in amyotrophic lateral sclerosis (ALS), and a central population damaged in spinal cord injury, a detailed understanding of the program of genetic controls regulating the generation and maturation of this specific projection neuron population is important both for fundamental understanding of brain organization and function, and for the potential future development of cellular repair strategies for ALS, spinal cord injury, and other diseases affecting CSMN.
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