Development of the Zebrafish Enteric Nervous System

斑马鱼肠神经系统的发育

• 批准号: 6953190
• 负责人: IAIN T SHEPHERD
• 金额: $ 32.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953190
• 关键词: cell differentiation; cell growth regulation; cell migration; chromosome walking; developmental genetics; developmental neurobiology; enteric nervous system; gene mutation; genetic regulation; genetically modified animals; molecular cloning; neural crest; neurogenesis; phenotype; site directed mutagenesis; tissue mosaicism; vertebrate embryology; zebrafish

Our long term goal is to understand how the vertebrate enteric nervous system (ENS) is specified and patterned during embryogenesis. Understanding the cellular and molecular processes involved in ENS formation will provide insights into how a complex structure, such as a nervous system arises, during development. Furthermore, our studies are of potential clinical importance in understanding the mechanisms and molecules that underlie pediatric conditions where the ENS fails to form correctly, such as Hirschsprung disease (HSCR). The ENS is derived from the neural crest, a multipotent population of cells that migrates from the neural tube along specific pathways to generate a wide variety of neural and non-neural tissues. Different axial populations of neural crest cells contribute to specific structures and tissues. In this proposal we will address where, when, and how ENS precursors are specified during embryogenesis. Our studies use the zebrafish due to the model system's cell biological, molecular and genetic strengths that are uniquely appropriate for our proposed experiments. Specifically, we aim to answer the following questions: 1) Do zebrafish enteric neural crest precursors arise from a distinct subset of vagal neural crest cells? We will determine the origin of the zebrafish ENS by lineage analysis. We will then investigate by cell transplantation the role of regulative interactions in specifying ENS precursor cell fate within the premigratory neural crest; 2) What gene is affected in the zebrafish ENS mutant, enema? We have identified several zebrafish mutants that have significant reductions in the number of enteric neurons. One of these mutants is enema another is lessen. We recently determined that lessen has a mutation in TRAP100. We will now identify the gene that is lesioned in enema that results in the mutant phenotype; 3) Which steps in ENS precursor development are affected in lessen and enema? We will characterize these mutants to determine cell biologically where, when, and how these mutations cause their phenotypes.Together the proposed aims will help increase our understanding of the mechanisms and molecules involved in generating the ENS and may provide valuable insights into the underlying causes of HSCR.

我们的长期目标是了解脊椎动物肠神经系统（ENS）是如何在胚胎发育过程中指定和模式化的。了解ENS形成所涉及的细胞和分子过程将提供对复杂结构（如神经系统）在发育过程中如何产生的见解。此外，我们的研究在理解ENS无法正确形成的儿科疾病（如先天性巨结肠症（HSCR））的机制和分子方面具有潜在的临床重要性。 ENS来源于神经嵴，神经嵴是从神经管沿沿着特定途径迁移以产生各种神经和非神经组织的多能细胞群。神经嵴细胞的不同轴向群体有助于特定的结构和组织。在这个建议中，我们将解决在哪里，何时，以及如何ENS前体指定在胚胎发生。我们的研究使用斑马鱼，因为模型系统的细胞生物学，分子和遗传优势，是唯一适合我们提出的实验。具体来说，我们的目标是回答以下问题：1）斑马鱼肠神经嵴前体产生于迷走神经嵴细胞的一个独特的子集？我们将通过谱系分析来确定斑马鱼ENS的起源。然后，我们将通过细胞移植的调节相互作用的作用，在指定ENS前体细胞的命运在premigration神经嵴; 2）什么基因是影响斑马鱼ENS突变，灌肠？我们已经确定了几个斑马鱼突变体，肠道神经元的数量显着减少。一 其中一种是灌肠剂，另一种是减脂剂。我们最近确定Less在TRAP 100中有突变。我们现在将确定在灌肠中损伤导致突变表型的基因; 3）ENS前体发育中的哪些步骤在灌肠和灌肠中受到影响？我们将描述这些突变体，以确定细胞生物学上这些突变在何处，何时，以及如何导致其phenotypes.Together提出的目标将有助于增加我们的理解的机制和参与产生ENS的分子，并可能提供有价值的见解HSCR的根本原因。