Many disorders of language are due to genetic aberrations; spoken and written language ability have significant genetic components in the general population. However, normal variation in language and language disorders tend to be complex, in that they are caused by multiple genes interacting with the environment. Recently a mutation in the FOXP2 gene was identified in a family with a speech and language development disorder including orofacial dyspraxia and grammar deficiencies. FoxP2 is a transcriptional represser in the forkhead binding domain containing family. Following the divergence of chimpanzees to humans, 2 coding variations resulting in amino acid changes occurred in FOXP2. These changes have undergone positive selection in the human lineage, therefore, it is hypothesized that these amino acid changes have in part led to the ability of humans to communicate with a spoken language. The functions of these changes at a systems or molecular level are not known. In addition, although Fox genes are known transcription factors, there are no known targets of FoxP2 in the brain. We expect that targets of the Foxp2 transcription factor will elucidate important players in the development of language and cognitive skills, as well as other features of brain development. We propose to perform chromatin immunoprecipitation (ChIP) with an antibody to FoxP2 followed by hybridization to a microarray with promoter sequences. We will specifically examine cerebral cortex and basal ganglia, regions where FoxP2 is known to be expressed in human during fetal brain development and that are abnormal in individuals with FoxP2 mutations. Gene expression analysis at the mRNA level will be used to confirm the Fox binding targets in vitro, and in situ hybridization and immunocytochemistry will be used to study co-expression of targets with FoxP2 in vivo. The effect of the 2 human specific changes will also be studied in vitro using site directed mutagenesis in a human neural cell line. Completion of the experiments described in this proposal will elucidate potential pathways through which FoxP2 acts, as well as the potential function of the human-specific variants with broad implications for our understanding of normal human brain development and disorders of language. This proposal has a strong screening component in an area where no molecular mechanisms have been identified and fits well within the R21 framework.
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