A significant number of individuals have unexplained difficulties with acquiring normal speech and language, despite adequate intelligence and environmental situation. There is substantial evidence for a genetic origin of these disorders. FOXP2 is the firs t, and to date only, gene which has been involved in a familiar form of speech and language impairment.
Although FOXP2 gene variants are unlikely to directly contribute to common forms of language impairment, this gene and its involvement in a severe for m of the disorder gives a novel insight into neural mechanisms contributing to speech and language. Since FOXP2 protein is a transcription factor, an obvious question to address is what are its downstream targets regulated during neuronal development.
The aim of this proposal is the identification of the downstream targets of this newly discovered transcription factor in brain tissue. For this purpose, we propose to take a variety of human neuronal-related cell-lines and to generate stable cell-lines in which we can induce over-expression of recombinant FOXP2 in a controlled manner. We will perform expression profiling of these modified cell-lines using micro-arrays to identify genes whose expression differs as a consequence of changes in FOXP2.
The most interesting target genes will then be validated by assessing the modification in their level of expression by quantitative RT-PCR, and by studying the activation/repression of their promoter by FOXP2 using luciferase reporter assay. The possible interactions between FOXP2 and other members of the FOXP family will also be studied to assess if the formation of heterodimers modify the expression profile. We expect to identify new genes, which may be involved in neuro-developmental disorders, what will contribute to the understanding of the basic molecular mechanisms underlying speech and language acquisition.
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