Ctip1 Function in Neocortical Projection Neuron Subtype Specification and Arealiz

Harvard Medical School, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The long-term goals of the proposed experiments are to elucidate molecular controls over neocortical projection neuron subtype specification and area identity acquisition, to investigate functions of Ctip1, a transcription factor that has been linked with autism spectrum disorders (ASD), and to potentially enable future approaches to repair degenerating, damaged, or developmentally abnormal neocortical circuits. The sophisticated circuits of the neocortex, which control higher-order brain functions, are built from an unparalleled diversity of neuronal subtypes, each with distinct morphologies, patterns of connectivity, and electrophysiological properties. Proposed experiments will deeply investigate a transcription factor of previously unknown function in the brain, Ctip1, in the specification and areal specialization of neocortical projection neurons. Ctip1 is a C2H2 zinc finger domain transcription factor identified in earlier microarray studies from our laboratory to be specificall expressed by callosal projection neurons (CPN), and largely excluded from corticospinal motor neurons (CSMN). This subtype-specific expression, along with its evolutionary conservation and previously-described functions controlling cell-type specific differentiation in other tissues, motivated further investigation into Ctip1 function. Substantial preliminary data is presented in this application to support all aims. I have already 1) examined the developmental time course, subtype specificity, and areal distribution of Ctip1 expression in the forebrain; 2) established tht Ctip1 interacts cross-repressively at the genetic level with close paralog Ctip2; 3) identified tha Ctip1 is sufficient to prevent layer V neurons from projecting subcerebrally; and 4) delineated striking subtype-specific gene expression abnormalities in Ctip1 null cortex. In addition, my data indicates that Ctip1 is necessary for 5) precise acquisition of molecular areal identity; 6) organization of thalamocortical input to sensory cortex; and 7) areal specificity of homotypic CPN connections. Proposed experiments will investigate possible functions ofCtip1 in CPN and corticothalamic projection neuron (CThPN) subtype-specific development (Aim 1) and in control over area identity acquisition by subcerebral projection neurons (SCPN), CThPN, and CPN, as well as thalamocortical innervation of primary sensory areas (Aim 2). These studies will further elucidate functions of the transcription factor Ctip1, a novel control over neocortical development.