Functional analysis of autism risk genes during neural development using single cell seq

大脑代表着一个复杂的器官，具有无数不同的功能 单元类型。自闭症谱系障碍(ASD)被认为改变了 转录和转录后代码负责指定和 维持脊椎动物大脑中不同的细胞功能。建议进行的研究 将检验染色质/转录调节因子识别的中心假设 因为ASD风险基因在早期起着发育开关的作用 神经发育，改变基因表达网络和后续细胞 功能。 在这项建议中，我们将单细胞测序与遗传、基因组 以及在斑马鱼和类胚体中的计算方法) 描述ASD危险基因在健康神经基因调控中的作用 网络(目标1)；2)询问ASD功能丧失(LOF)的影响 不同神经谱系的突变(目标2)。细胞类型与发育 大脑中受每个候选人影响更大的血统 将利用斑马鱼和人类细胞来源的细胞鉴定ASD风险基因 有机化合物。 这项提案中概述的实验的最终目标是 确定ADS风险基因如何影响神经基因表达和细胞功能 在脊椎动物的发育过程中。

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.