Impaired cognition, and in particular language, is a hallmark of common neuropsychiatric diseases such as autism and schizophrenia;however, the molecular mechanisms underlying higher cognitive function development and evolution in humans remain unknown. The elucidation of signaling pathways that are important for language and cognition will provide targets for future therapeutics. Frontal-striatal circuitry is critical for normal cognitive function and is frequently disrupted in neuropsychiatric disease. The transcription factor F0XP2 is the only gene currently identified that is mutated in patients with isolated language disturbances, and it has high expression in both frontal and striata) regions of developing human brain. Current data supports a role for both F0XP2 and its regulation of genes involved in autism and schizophrenia, The research in this proposal will focus on the developmentally regulated signaling pathways downstream of FbXP2 and how perturbations to these pathways result in cognitive defects in both ASD and schizophrenia, the specific aims include: 1) Identify the signaling pathways regulated by F0XP2 in human neurons, and which of these pathways are important for neuronal differentiation and/or maintenance, 2) Determine evolutionarily conserved and human-specific F0XP2 targets by conducting comparative whole gene transcriptome sequencing and F0XP2 promoter binding in fetal human, rhesus macaque, and mouse brain, and 3) Ascertain how Fdxp2 and Foxpl cooperatively regulate gene expression during CNS development by generating Foxpl conditional knockout mice and conducting genome wide Foxp2 promoter binding analysis.
To Public Health Autism spectrum disorders and schizophrenia are two of the most common cognitive disorders in the United States and worldwide. Proper brain development is critical for cognition and these developmental processes are vulnerable to disruptions, which subsequently lead to mental illness. These proposed studies will provide insight into the developmental mechanisms underlying cognition and how they are disrupted in mental illness.
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