Language is a specialized mental faculty that enables humans to arrange and communicate thoughts through the use of different modalities such as sounds or symbols. Numerous studies have shown that several regions in the neural system might be responsible for the processing and production of speech and language. However, studies on the development and organization of the complex underlying neuronal circuitry at the cellular and molecular levels have been technically challenging. Recent reports by other groups and preliminary results generated in my laboratory provided us with an opportunity to undertake such an analysis. We have identified a small population of cortical pyramidal neurons present in the human fetal speech-related cortical region. These neurons are uniquely identified by the combinatorial expression of Forkhead Box P2 (FOXP2), haploinsufficiency in which can lead to a severe speech disorder, Nitric Oxide Synthase 1 (NOS1), and ZNF312, a novel layer V-specific transcription factor. Based on the areal and laminar position of these neurons, as well as their gene expression, we hypothesize that they are a central component in the circuitry that mediates language processing and speech production. In this grant application, we propose to characterize the functional roles of transcription factors FOXP2 and ZNF312 in the development, refinement and maintenance of that corticostriatal and corticothalamic circuits. In the first specific aim of this proposal, we propose to analyze the organization and distribution of FOXP2-positive corticofugal projections in the primate ventrolateral frontal cortex. In the second aim, we propose to determine the role of FOXP2 in the refinement and maintenance of corticostriatal and corticothalamic projections. In the third specific aim, we propose to determine the role of zinc finger protein, ZNF312, in the formation and corticostriatal and corticothalamic projections. The elucidation of how FOXP2 and ZNF312 may regulate development of neural pathways involved in spoken language as outlined in this proposal will help in understanding normal brain development and the neurobiological foundations of speech and language. This research may further facilitate the identification of additional disease genes and the development of new therapeutic strategies for the treatment of speech and motorrelated disorders ? ?
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