SACRAL CREST CELLS AND ENTERIC NEURODEVELOPMENT

骶嵴细胞和肠神经发育

• 批准号: 6517990
• 负责人: RAJ P. KAPUR
• 金额: $ 20.86万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517990
• 关键词: developmental genetics; developmental neurobiology; ganglion cell; gastrointestinal motility /pressure; gastrointestinal system; genetically modified animals; immunocytochemistry; laboratory mouse; mutant; neural crest; neurogenetics; neuroregulation; transcription factor; vertebrate embryology

DESCRIPTION (Applicant's Abstract): Hirschsprung disease, hypoganglionosis, intestinal neuronal dysplasia and other disorders of intestinal motility are characterized by defects in the enteric nervous system, particularly in the large intestine. The complex nervous network in this region contains biochemically and electrophysiologically distinct classes of neurons, which derive embryologically from vagal or sacral neural crest lineages. The investigator has developed a model system to discriminate vagal and sacral crest-derived neurons in explants of murine embryonic large intestinal segments that are allowed to develop under the adult renal capsule. The investigator hypothesizes that enteric neurons, derived from sacral crest, are biochemically and functionally distinct from other intestinal ganglion cells. The subcapsular system will be used to investigate immunohistochemically the neuronal and/or glial phenotypes of neurons produced by sacral crest cells and compare them with the phenotypes of vagal crest cells. A candidate marker for sacral crest-derived neurons that may determine their phenotype is the transcription factor, Hox11L1; because it is putatively expressed in ganglion cells of the post-umbilical gut, but not more proximal bowel. More importantly, mice lacking Hox11L1 have intestinal hyperganglionosis and die from intestinal pseudo-obstruction and may serve as a model for some forms of human intestinal dysmotility. This group has created transgenic mice that will be used to determine whether Hox11L1-expression is a specific property of sacral crest-derived neurons. The investigator will determine the influence of Hox11L1 on neuronal differentiation, including transmitter phenotypes and neuroanatomical properties. A heterologous promoter will be used to express Hox11L1 ectopically and determine the transcription factor's influence on the properties of other classes of enteric ganglion cells. In addition, a transgenic model will be created to examine the fates, in Hox11L1 -/- mice, of cells that would normally express Hox11L1. The results of this study will further our understanding of normal enteric neurodevelopment and congenital disorders of intestinal motility.

描述（申请人摘要）：先天性巨结肠，神经节细胞减少症， 肠神经元发育不良和其它肠运动障碍， 其特征在于肠神经系统缺陷，特别是 大肠这个区域的复杂神经网络包含 生物化学和电生理学上不同类别的神经元， 胚胎学上起源于迷走神经或骶神经嵴谱系。的 研究者开发了一个模型系统来区分迷走神经和骶神经 小鼠胚胎大肠肠段移植中嵴源性神经元的研究 可以在成人肾包膜下生长研究者 假设肠神经元，来自骶嵴，是生化 并且在功能上不同于其他肠神经节细胞。被膜下 系统将被用来研究神经元和/或 骶嵴细胞产生的神经元的胶质细胞表型，并比较它们 迷走嵴细胞的表型骶骨的候选标记物 嵴源性神经元的转录可能决定其表型 因子Hox 11 L1;因为它是puristic表达在神经节细胞的 脐后肠但没有近端肠更重要的是，老鼠缺乏 Hox 11 L1具有肠神经节过多症，并死于肠神经节变性， 假梗阻，并可作为某些形式的人类肠 运动障碍这个小组已经创造了转基因小鼠， 确定Hox 11 L1表达是否是骶骨的特异性特性， 嵴源神经元研究者将确定Hox 11 L1的影响 神经元分化，包括递质表型和 神经解剖学特性异源启动子将用于表达 Hox 11 L1异位表达，并确定转录因子对Hox 11 L1异位表达的影响。 其他类型的肠神经节细胞的特性。另外还有按 将建立转基因模型，以检查Hox 11 L1-/-小鼠中 正常表达Hox 11 L1的细胞。这项研究的结果将 进一步了解正常肠神经发育和先天性 肠道运动障碍。