ROLE OF TFII-I IN CRANIOFACIAL DEVELOPMENT

TFII-I 在颅面发育中的作用

基本信息

批准号：
7146517
负责人：
DASHZEVEG BAYARSAIHAN
金额：
$ 37万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7146517
关键词：
alleles craniofacial gene targeting genes neural crest role

项目摘要

DESCRIPTION (provided by applicant): Craniofacial related birth defects account for 1/3rd of all congenital anomalies. Defects in neural crest cells (NCC) cause most of these disorders; however, the signaling pathways involved in craniofacial morphogenesis are poorly understood. Therefore, knowledge of the molecular mechanisms of neural crest development is necessary to understand human craniofacial disorders. Our long-term goal is to identify the regulatory pathways that instruct NCC morphogenesis. The objective of this application is to determine the molecular and genetic role of the TFII-I transcription factor in craniofacial development. Deletion of the Gtf2i allele, which encodes this protein causes craniofacial defects in mice. TFII-I regulates the transcription of target genes via interactions with histone deacetylases and Smad2 and is expressed in neural crest-derived tissues. We hypothesize that 1 of the roles of TFII-I is to control signaling cascades critical for neural crest morphogenesis. We, therefore, propose an in depth analysis of Gtf2i to understand its role during neural crest development. First, molecular and cellular changes underlying craniofacial defects will be analyzed in mutant embryos. Second, a set of downstream target genes regulated by TFII-I in cranial NCC will be identified using microarray and chromatin immunoprecipitation analysis. Third, the Gtf2i allele will be abrogated in the NCC lineage with the conditional Cre/LoxP recombination system. The outcome of the proposed research will allow us to identify the TFII-l-dependent genes and signaling pathways involved in the morphogenesis of neural crest-derived structures. These studies will provide a better understanding of craniofacial genetic pathways and pathogenesis of human birth defects.

描述（由申请人提供）：颅面相关出生缺陷占所有先天异常的 1/3。大多数此类疾病都是由神经嵴细胞 (NCC) 缺陷引起的。然而，人们对颅面形态发生中涉及的信号通路知之甚少。因此，了解神经嵴发育的分子机制对于了解人类颅面疾病是必要的。我们的长期目标是确定指导 NCC 形态发生的调控途径。本应用的目的是确定 TFII-I 转录因子在颅面发育中的分子和遗传作用。编码该蛋白的 Gtf2i 等位基因的缺失会导致小鼠颅面缺陷。 TFII-I 通过与组蛋白脱乙酰酶和 Smad2 相互作用调节靶基因的转录，并在神经嵴衍生组织中表达。我们假设 TFII-I 的作用之一是控制对神经嵴形态发生至关重要的信号级联。因此，我们建议对 Gtf2i 进行深入分析，以了解其在神经嵴发育过程中的作用。首先，将分析突变胚胎中颅面缺陷的分子和细胞变化。其次，将使用微阵列和染色质免疫沉淀分析来鉴定颅内 NCC 中由 TFII-I 调节的一组下游靶基因。第三，NCC谱系中的Gtf2i等位基因将通过条件Cre/LoxP重组系统被废除。拟议研究的结果将使我们能够识别参与神经嵴衍生结构形态发生的 TFII-1 依赖性基因和信号通路。这些研究将有助于更好地了解颅面部遗传途径和人类出生缺陷的发病机制。