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.

Public Health Relevance

The proposed research investigating functions of the transcription factor Ctip1 during development of the cerebral cortex has significant clinical implications and is of great interest for the field of developmental neurobiology, since a detailed understanding of molecular controls programs regulating generation, maturation and areal specialization of neocortical projection neuron subtypes will be important toward elucidating the basic biology of cerebral cortex development, organization, evolution, and function, and also toward informing future cellular therapeutic strategies for neurodegenerative disorders. Preliminary experiments demonstrate that interhemispheric connections develop abnormally in the absence of Ctip1 function, indeed, mutations in Ctip1 have been linked to autism spectrum disorders (ASD) in genetic epidemiological studies, consistent with emerging hypotheses in the field that defective associative connectivity is a common underlying pathology in patients with ASD. In addition, because Ctip1 mutant mice have a reduced corpus calosum and Probst bundles, and because callosal projection neurons establish aberrant heterotypic connections in the absence of Ctip1 function, Ctip1 mutant mice might prove to be a particularly informative model for partial agenesis of the corpus callosum, a neurodevelopmental disorder affecting 1 in 4000 newborns.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Mamounas, Laura
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Harvard University
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Woodworth, Mollie B; Greig, Luciano C; Liu, Kevin X et al. (2016) Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. Cell Rep 15:999-1012
Greig, Luciano C; Woodworth, Mollie B; Greppi, Chloé et al. (2016) Ctip1 Controls Acquisition of Sensory Area Identity and Establishment of Sensory Input Fields in the Developing Neocortex. Neuron 90:261-77
Greig, Luciano Custo; Woodworth, Mollie B; Galazo, Maria J et al. (2013) Molecular logic of neocortical projection neuron specification, development and diversity. Nat Rev Neurosci 14:755-69
Woodworth, Mollie B; Custo Greig, Luciano; Kriegstein, Arnold R et al. (2012) SnapShot: cortical development. Cell 151:918-918.e1