SACRAL CREST CELLS AND ENTERIC NEURODEVELOPMENT

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他肠道运动障碍 以肠道神经系统缺陷为特征的，尤其是在 大肠。这一区域复杂的神经网络包含 在生物化学和电生理上不同类别的神经元，它们 从胚胎学上讲，来源于迷走神经或骶神经脊谱系。这个 研究人员开发了一种区分迷走神经和骶骨的模型系统 小鼠胚胎大肠段外植体中CREST来源的神经元 它们可以在成人肾被膜下发育。调查员 从生物化学的角度假设，来源于骶骨顶的肠神经元。 在功能上有别于其他肠神经节细胞。包膜下 系统将用于免疫组织化学研究神经元和/或 骶棘细胞产生的神经元的神经胶质表型及其比较 迷走神经脊细胞的表型。骶骨的候选标记 决定其表型的可能是CREST来源的神经元的转录 因子Hox11L1；因为它可能在大鼠神经节细胞中表达。 脐带后的肠道，但不是更近端的肠道。更重要的是，老鼠缺乏 Hox11L1患有肠神经节细胞增多症并死于肠道 假性肠梗阻，可作为某些形式的人体肠道疾病的模型 运动障碍。这个小组创造了转基因小鼠，将被用来 确定Hox11L1-表达是否是骶骨的特异属性 冠状突起神经元。研究人员将确定Hox11L1病毒的影响 关于神经元分化的研究，包括递质表型和 神经解剖学特征。将使用异源启动子来表达 Hox11L1的异位表达，并确定转录因子对Hox11L1的影响。 其他类型的肠神经节细胞的特性。此外，a 将建立转基因模型来检测Hox11L1-/-小鼠的命运 正常表达Hox11L1的细胞。这项研究的结果将 加深对正常肠神经发育和先天性的认识 肠道运动障碍。

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.