FUNCTION OF CX43-INTERACTING PROTEINS IN NEURAL CREST MIGRATION

CX43 相互作用蛋白在神经嵴迁移中的功能

基本信息

批准号：
7335624
负责人：
ROBERT G GOURDIE
金额：
$ 35.44万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2006-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7335624
关键词：
Actin-Binding Protein Actins Adenoviruses Adherent Culture Affect Authorization documentation Behavior Binding C-terminal Cardiac Cardiovascular system Cells Characteristics Chick Embryo Complementary DNA Computer Systems Development Congenital Abnormality Connexin 43 Connexins Coupling Cytoskeleton Data Development Drosophila genus Embryo Ensure Epithelial Cells FGF8 gene Fibroblast Growth Factor 8 Fibroblasts Gap Junctions Grant Green Fluorescent Proteins Heart Homocysteine Homocystine Human Immigration In Vitro Mediating Migration Assay Molecular Morphogenesis Mus Myocardial N-terminal NIH 3T3 Cells Neural Crest Neural Crest Cell Neural tube PDZ protein Pattern Peptides Principal Investigator Protein Binding Proteins Publishing Rate Regulation Reporting Resources Role Testing Transgenic Mice Translations Tumor Suppressor Proteins United States National Institutes of Health Work base cardiogenesis cell motility cell type concept design driving force in vivo insight migration mouse model mutant novel programs tool wound

项目摘要

Proper coordination of neural crest migration is an absolute requirement for normal cardiovascular development - most particularly outflow tract morphogenesis. The gap junction protein Cx43 has a key function in this directed migration of cardiac neural crest cells. The molecular mechanism by which Cx43 affects neural crest motility is unknown. The forces driving cell migration are generated largely by the dynamics of the actin cytoskeleton. We hypothesize that proteins mediating linkage between connexins and actin are candidates for regulators of cell motility. One molecule known to mediate interaction between connexins and actin is ZO1 - a PDZ protein related to the Drosophila tumor suppressor protein discs large. The Gourdie lab has shown that Cx43-ZO1 interaction is critical to developmental remodeling of the extentof gap junctional contact between myocardial cells. Furthermore, we have data showing that inhibition of ZO1- Cx43 interaction decreases neural crest outgrowth in vitro and reduces motility of fibroblasts and epithelial cells in cultured monolayers in a "scratch wound" migration assay. We will test the hypothesis that ZO1-Cx43 interaction is an integral part of a mechanism involved in regulation of cell-cell contact pattern and migration of neural crest cells by determining: 1. Whether factors known to stimulate neural crest cell motility, affect interactions between Cx43, ZO-1 and other connexin interacting proteins in vitro; 2. Whether inhibition of ZO1-Cx43 interaction is sufficient to disrupt regulation of the rate and directionality of neural crest cell migration in vitro; and 3. if ZO1-Cx43 interaction is necessary for the directed migration of neural crest cells in vivo. This study will provide new insight into molecular regulation of neural crest migration in the embryo and origins of birth defects in humans. ;

神经rest迁移的适当协调是正常心血管的绝对要求发展 - 尤其是流出的形态发生。间隙连接蛋白CX43具有钥匙在这种定向的心脏神经rest细胞的迁移中起作用。 CX43的分子机制影响神经rest运动尚不清楚。驱动细胞迁移的力主要由肌动蛋白细胞骨架的动力学。我们假设蛋白质介导连接素和肌动蛋白是细胞运动调节剂的候选者。一个已知可以介导的分子连接蛋白和肌动蛋白是ZO1-一种与大型果蝇抑制蛋白蛋白盘相关的PDZ蛋白。 Gourdie实验室表明，CX43-ZO1相互作用对于范围的发展重塑至关重要心肌细胞之间的间隙连接接触。此外，我们还有数据表明抑制ZO1- CX43相互作用可在体外减少神经rest柱出现，并降低成纤维细胞和上皮的运动性培养的单层中的细胞中的“刮擦伤”迁移分析中的细胞。我们将测试ZO1-CX43的假设相互作用是涉及细胞电池接触模式调节机制的组成部分通过确定神经rest细胞的神经rest细胞：1。是否已知的因素刺激神经rest细胞运动，影响在体外，CX43，ZO-1和其他连接蛋白相互作用蛋白之间的相互作用； 2。是否抑制 ZO1-CX43相互作用足以破坏对神经Crest细胞速率和方向性的调节体外迁移； 3。如果ZO1-CX43相互作用对于神经rest细胞的定向迁移是必需的体内。这项研究将为胚胎中神经rest迁移的分子调节提供新的见解和人类出生缺陷的起源。 ;