Development of the Zebrafish Enteric Nervous System

斑马鱼肠神经系统的发育

• 批准号: 7036409
• 负责人: IAIN T SHEPHERD
• 金额: $ 2.5万
• 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/7036409
• 关键词: Development; Zebrafish; Enteric; Nervous; System

DESCRIPTION (provided by applicant): 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's 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 all 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 ablation and cell transplantation the role of regulative interactions in specifying ENS precursor cell fate within the premigratory neural crest; 2) Which steps in enteric precursor development are affected by two mutations, lessen and enema? We have identified two zebrafish mutants that have significant reductions in the number of enteric neurons. We will characterize these mutants to determine cell biologically where, when, and how these mutations cause their ENS phenotypes; 3) What genes are affected in the lessen and enema mutants? We will identify the genes that are lesioned in lessen and enema and result in the ENS phenotype observed. 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

描述（由申请人提供）：我们的长期目标是了解脊椎动物肠神经系统（ENS）在胚胎发生过程中是如何被指定和模式化的。了解ENS形成所涉及的细胞和分子过程将有助于深入了解复杂结构（如神经系统）在发育过程中如何产生。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））的机制和分子基础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）所有的斑马鱼肠神经嵴前体产生的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，我们将调查细胞消融和细胞移植的作用，在指定ENS前体细胞的命运在premigration神经嵴的调节相互作用; 2）在肠道前体发展的步骤是由两个突变，减轻和灌肠的影响？我们已经确定了两个斑马鱼突变体，肠道神经元的数量显着减少。我们将这些突变体的特点，以确定细胞生物学在何处，何时，以及如何这些突变导致他们的ENS表型; 3）什么基因受到影响的减轻和灌肠突变体？我们将确定在减轻和灌肠中受损的基因，并导致观察到的ENS表型。总之，提出的目标将有助于增加我们对产生ENS的机制和分子的理解，并可能为HSCR的根本原因提供有价值的见解