The brain represents a complex organ with a myriad of functionally diverse cell types. Autism spectrum disorder (ASD) is thought to alter the combinatorial transcriptional and post-transcriptional code responsible for specifying and maintaining different cell functions in the vertebrate brain. The proposed studies will test the central hypothesis that chromatin/transcriptional regulators identified as ASD risk genes act as developmental switches during early neurodevelopment, altering the gene expression network and subsequent cell function. In this proposal we combine single cell sequencing, with genetic, genomic and computational approaches in zebrafish and embryoid bodies to i) characterize the role of ASD-risk genes in healthy neural gene regulatory networks (Aim 1); 2) Interrogate the effects of ASD loss-of-function (LOF) mutations in different neural lineages (Aim 2). Cell types and developmental lineages within the brain that are more significantly affected by each candidate ASD risk gene will be identified using zebrafish and human cell?derived organoids. The experiments outlined in this proposal have the ultimate goal of identifying how ADS risk genes affect neural gene expression and cell function during vertebrate development.
Autism is a neurodevelopment disorder, yet the cell types that are affected by different mutations identified in human are poorly understood. In this proposal we will investigate how mutation in ASD risk genes affect the expression of different genes across the different neuronal cells during development using cell culture and vertebrate embryos in zebrafish. The results derived from this proposal are likely to provide key insights into the basic mechanism of shaping gene expression in the normal brain and in ASD affected brains.
