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Genetic Studies of Cortex Structure and Development

皮层结构和发育的遗传学研究

基本信息

批准号：
9360012
负责人：
JOHN L. R. RUBENSTEIN
金额：
$ 63.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360012
关键词：
Autistic Disorder Automobile Driving Binding Binding Proteins Biological Assay CRISPR/Cas technology Cell Separation Cell physiology Cells Cerebral Palsy Cerebral cortex Code DNA sequencing Development Embryo Enhancers Epilepsy Fibroblast Growth Factor Foundations Gene Expression Regulation Gene Targeting Generations Genes Genetic Genetic Enhancer Element Genetic Transcription Genetic study Histones Human Human Genetics Mental Retardation Mental deficiency Mitotic Molecular Mutation Nature Neurons Pathway interactions Pattern Phenotype Regulator Genes Regulatory Element Research Role Schizophrenia Signal Transduction Structure Testing Transcriptional Regulation Transgenic Mice Translating Ventricular Work chromatin immunoprecipitation developmental disease emx2 protein epigenomics experimental study genetic information genetic variant in vivo insight loss of function loss of function mutation mutant neuropsychiatric disorder progenitor promoter public health relevance response subventricular zone transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY Dysregulation of the cerebral cortex is central to human developmental disorders such as epilepsy, mental deficiency, autism and schizophrenia. During development, cortical progenitors generate the projection neurons of the different cortical subdivisions. Understanding the genetic circuitry controlling the development and function of these neurons provides an essential foundation for interpreting human allele variants that are enriched in people who have neuropsychiatric disorders. To elucidate this genetic circuitry, we must define the transcription factors (TF), and regulatory elements and of the coding regions that they control. The proposed research, which concentrates on cortical regionalization, involves the systematic identification of TFs, and the regulatory elements and genes downstream of TFs. Currently, the regional-specification functions of a few TFs in embryonic cortical progenitors are known, and little is known about their direct transcription targets, the nature of the regulatory elements that these TFs control, and the transcriptional circuitry that integrates development and function of these cells. Here we propose to make inroads into each of these components of the TF hierarchy regulating cortical development. Furthermore, we aim to elucidate transcriptional mechanisms through which patterning of cortical progenitors is transmitted to, and maintained in, cortical neurons. We hypothesize that enhancers active in the ventricular zone, subventricular zone and the cortical plate are differentially bound by TFs that drive expression of region/layer-specific genes in post-mitotic cortical neurons. The enhancers serve as protein-binding modules that translate rostrocaudal gradients of TFs in cortical progenitors into region-specific expression in cortical neurons. Herein we focus on the transcriptional mechanisms controlling the generation of different regions of the cerebral cortex (cortical regionalization). The Five Specific Aims extend upon our earlier work on regionalization of cortical progenitors by FGF-signaling, TFs and enhancer elements. Here we investigate transcriptional regulation of cortical patterning by defining the TFs, and other genes, that are regulated by COUPTF1, EMX2, and PAX6 (Aim 1). We then use chromatin immunoprecipitation-DNA sequencing (ChIP-Seq) to define the regulatory element (RE) and gene targets of COUPTF1, EMX2, and PAX6 (Aim 2). Next, we use fluorescent activated cell sorting (FACS) to purify cells from the VZ, SVZ, CP and layers 5&6 to elucidate the epigenomic states of REs (and genes) using Histone ChIP-Seq. This will help us understand the molecular mechanisms that transmit regional patterning information from cortical progenitors to neurons (Aim 3). Finally, we define the function of REs related to cortical patterning using transgenic mice to assess RE activity (Aims 4) and REs deletions to define their role in gene regulation (Aim 5). Once integrated with human genetic information, this will enable us to gain powerful insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders.

项目总结