Complete knowledge of the signaling pathways underlying brain development still remains unknown. The long- term goal of our laboratory is to elucidate the molecular signaling pathways disrupted in neurodevelopmental disorders that are important for brain development. Mutations in the gene encoding FOXP1 have previously been identified in individuals with developmental delay, intellectual disability, and autism. Our preliminary studies have shown that the transcription factor FOXP1 regulates genes important in brain development, and reduction in FOXP1 levels leads to behavioral changes in rodents. In addition, our data show that Foxp1 is a critical regulator of genes important for neuronal activity and loss of Foxp1 results in altered neuronal function. Based on these data, the central hypothesis driving this proposal is that FOXP1 is an orchestrator of transcriptional signaling cascades that are important for neuronal function and are at risk in neurodevelopmental disorders such as ASD. We propose to identify the developmental and regional disease-relevant targets of FOXP1 in the developing brain by using a combination of rodent models and human transcriptome data through three specific aims: 1) Identify the developmental transcriptional program regulated by Foxp1 in the brain; 2) Assess the role of Foxp1 and target genes in activity-dependent neuronal function; and 3) Determine the regional contribution of Foxp1 in the brain to specific ASD-relevant behaviors. Together, these aims will determine the transcriptional program regulated by Foxp1 throughout brain development and how Foxp1 gene regulation may be related to neuronal function and specific disease- relevant behaviors. Completion of the proposed aims will provide increased knowledge as to the molecular pathways that can be targeted for treatment in individuals with autism. The generated rodent models can be utilized to examine new therapeutic approaches for reversing autism-relevant behaviors. These data will also provide insight into the basic molecular mechanisms governing normal brain development.
Autism spectrum disorders is the most common, heritable, childhood-onset neuropsychiatric disorder. Understanding the genes and molecules critical for normal brain development will provide insight into the etiology of autism and other developmental brain disorders. These proposed studies will elucidate genes and molecular pathways important in brain development that can be targeted for the treatment of autism and other neurodevelopmental disorders.
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