BEN factors are conserved CSL co-repressors in Notch-mediated neural development

BEN 因子是 Notch 介导的神经发育中保守的 CSL 共抑制因子

基本信息

批准号：
8730239
负责人：
Eric C Lai
金额：
$ 42.97万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730239
关键词：
Address Adult Affect Animals Binding Biochemical Biochemical Genetics Bioinformatics Biological Assay Biological Models Brain Cell Communication Cell Count Cells ChIP-seq Chicago Chromatin Collaborations Complement Complex DNA Binding Data Development Drosophila genus Embryo Enhancers Event Family Future Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genome Goals Individual Invertebrates Knowledge Laboratories Learning Light Location Logic Maps Mediating Modeling Molecular Molecular Genetics Mus Neocortex Nervous system structure Neurons Notch Signaling Pathway Nuclear Protein Organ Pathway interactions Pattern Peripheral Nervous System Phenotype Philosophy Positioning Attribute Post-Transcriptional Regulation Property Protein Family Proteins Radial Reagent Regulator Genes Regulatory Element Reporter Repression Role SKI gene Sensory Sequence Analysis Signal Pathway Signal Transduction Small RNA Specific qualifier value System Techniques Tertiary Protein Structure Testing Tissues Validation Work fly gene repression genetic analysis genome-wide in vivo inhibitor/antagonist insight intercellular communication loss of function nerve stem cell nervous system development neural patterning neurodevelopment neurogenesis notch protein novel progenitor receptor relating to nervous system self-renewal stem cell division subventricular zone transcription factor

项目摘要

DESCRIPTION (provided by applicant): BEN factors are conserved CSL co-repressors in Notch-mediated neural development. Our general goal is to understand how cell signaling pathways mediate accurate transcriptional gene control during development. We focus on the Notch signaling pathway and its roles in directing neural cell fates and states. We strive to elucidate general principles of gene regulation by combining studies in both Drosophila and mammalian model systems. This proposal describes first in vivo functional studies of BEN-solo domain proteins. From our Drosophila work, we found that the BEN-solo factor Insensitive (Insv). regulates Notch signaling and peripheral nervous system development by acting as a direct corepressor for the Notch transcription factor CSL. We will further study its genetic requirements, dissect its functional domains, and elucidate how it cooperates with other chromatin factors to induce transcriptional repression. We build upon this proprietary knowledge to study roles of mammalian BEN-solo factors during neural development, and we have preliminary data on their ability to inhibit Notch signaling and affect neural stem cell self-renewal and differentiation. These phenotype-driven studies will be complemented by genomewide analyses of chromatin binding of CSL and BEN-solo factors in flies and mice, from which we will extract Notch-regulated enhancers. We will validate enhancers in vivo with emphasis on neural regulatory elements. We hope to determine conserved features of N/CSL/BEN target networks in the nervous system. In addition, these data potentially shed light on CSL-independent association of BEN-solo proteins with chromatin, which we will address using functional assays. Overall, this proposal combines a variety of experimental approaches and model systems to investigate a novel conserved neural corepressor in the Notch pathway.

描述（由申请人提供）：BEN因素是Notch介导的神经发育中保守的CSL共抑制剂。我们的总体目标是了解细胞信号通路如何介导开发过程中准确的转录基因控制。我们专注于Notch信号通路及其在指导神经细胞命运和状态中的作用。我们努力通过结合果蝇和哺乳动物模型系统的研究来阐明基因调节的一般原理。该提案描述了Ben-Solo结构蛋白的首次体内功能研究。从我们的果蝇工作中，我们发现Ben-Solo因子不敏感（INSV）。通过充当Notch转录因子CSL的直接核压剂来调节Notch信号传导和周围神经系统的发育。我们将进一步研究其遗传需求，剖析其功能域，并阐明其与其他染色质因子如何诱导转录抑制作用。我们基于这些专有知识，以研究神经发育过程中哺乳动物ben-solo因素的作用，并且我们有关于它们抑制Notch信号传导和影响神经干细胞自我更新和分化的能力的初步数据。这些表型驱动的研究将通过蝇和小鼠中CSL和Ben-Solo因子的染色质结合的分析来补充，从中我们将提取缺口调节的增强剂。我们将在体内验证增强子，重点是神经调节元件。我们希望确定神经系统中N/CSL/BEN目标网络的保守特征。此外，这些数据可能会阐明Ben-Solo蛋白与染色质的CSL无关的关联，我们将使用功能测定法解决。总体而言，该建议结合了各种实验方法和模型系统，以研究Notch途径中新型的保守神经核压剂。