FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions

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DESCRIPTION (provided by applicant): 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 FOXP2 is the only gene currently identified that is mutated in patients with isolated language disturbances, and it has high expression in both frontal and striatal regions of developing human brain. Current data supports a role for both FOXP2 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 FOXP2 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 FOXP2 in human neurons, and which of these pathways are important for neuronal differentiation and/or maintenance, 2) Determine evolutionarily conserved and human-specific FOXP2 targets by conducting comparative whole gene transcriptome sequencing and FOXP2 promoter binding in fetal human, rhesus macaque, and mouse brain, and 3) Ascertain how Foxp2 and Foxp1 cooperatively regulate gene expression during CNS development by generating Foxp1 conditional knockout mice and conducting genome wide Foxp2 promoter binding analysis. This proposal contains a detailed five year training plan and research proposal outlining how the principle investigator will acquire new skills in recent technology, complete current studies, lay the foundation for independent studies, and transition to an independent investigator position to study the molecular genetics of neuropsychiatric illnesses. The principle investigator is a skilled molecular and cell neurobiologist with training in animal models and bioinformatic analysis of gene expression data. Under the mentorship of Dr. Daniel Geschwind, the principle investigator will learn and implement next generation sequencing technologies. Dr. Geschwind is an internationally renowned leader in the field of neurogenetics, in particular autism genetics, and his laboratory has published extensively on complex analysis of brain gene expression studies. In addition, an advisory committee of distinguished UCLA faculty members will provide scientific and career guidance. Together, the Department of Neurology and Brain Research Institute at UCLA will provide all of the resources needed to successfully complete this training plan including highly regarded scientists, core facilities, and an active didactic community. PUBLIC HEALTH RELEVANCE: 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.