SACRAL CREST CELLS AND ENTERIC NEURODEVELOPMENT

骶嵴细胞和肠神经发育

• 批准号: 6635406
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635406
• 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）：先天性巨结肠症、神经节减退症、 肠道神经元发育不良和其他肠道动力障碍是 以肠神经系统缺陷为特征，特别是 大肠。该区域复杂的神经网络包含 生物化学和电生理学上不同类别的神经元， 胚胎学上源自迷走神经或骶神经嵴谱系。这 研究人员开发了一个模型系统来区分迷走神经和骶神经 小鼠胚胎大肠段外植体中嵴源性神经元 允许在成人肾囊下发育。调查员 假设源自骶嵴的肠神经元在生化上具有 并且在功能上与其他肠神经节细胞不同。被膜下 系统将用于通过免疫组织化学研究神经元和/或 骶嵴细胞产生的神经元的胶质表型并进行比较 与迷走神经嵴细胞的表型。骶骨的候选标记 可能决定其表型的嵴衍生神经元是转录 因子，Hox11L1；因为它被认为在神经节细胞中表达 脐后肠，但不是更近端的肠。更重要的是，小鼠缺乏 Hox11L1患有肠道神经节亢进症并死于肠道 假性梗阻，可以作为某些形式的人类肠道的模型 运动障碍。该小组创造了转基因小鼠，将用于 确定 Hox11L1 表达是否是骶骨的特定属性 嵴源性神经元。研究者将确定 Hox11L1 的影响 神经元分化，包括递质表型和 神经解剖学特性。将使用异源启动子来表达 Hox11L1 异位并确定转录因子对 其他类别肠神经节细胞的特性。此外，还有一个 将创建转基因模型来检查 Hox11L1 -/- 小鼠的命运 通常表达 Hox11L1 的细胞。这项研究的结果将 进一步加深我们对正常肠神经发育和先天性的了解 肠道蠕动障碍。