Development of the enteric nervous system

肠神经系统是周围神经系统中最大、最复杂的部分。它遍布整个肠道，并负责正常的肠道运动。因此，肠系系统的异常发育是神经节性巨结肠等肠道运动障碍的主要原因。这种致命的情况是由于在肠道末端区域缺乏完整的ENS引起的；受影响的节段保持收缩，导致肠梗阻、扩张和严重便秘。人类临床病例和动物模型已经鉴定出几个对ENS发育重要的基因。然而，考虑到ENS的复杂性，我们对其形成的理解还远远不够。为了确定对ENS发展重要的新基因/位点，我在转基因小鼠中进行了插入突变筛选。由于在小鼠基因组中随机插入转基因，该筛选允许鉴定出显示神经节巨结肠表型的三种小鼠，称为“Dapple”，“Dominant Spot”和“Holstein”。迄今为止的遗传研究表明，至少在新的基因/位点上出现了Dapple和显性斑的突变。提出的研究计划旨在鉴定和表征受这些突变影响的基因，特别关注Dapple系。迄今为止的分子研究表明，新基因Kiaa1279的表达减少是Dapple巨结肠表型的原因。在这方面，我现在建议研究了解Kiaa1279基因产物在ENS发展中的功能。总的来说，这项研究计划将显著扩展目前在遗传、分子和细胞水平上对ENS发展的有限知识。这一新知识将为加拿大目前尚未充分研究的重要研究领域做出关键贡献。

The enteric nervous system is the largest and most complex part of the peripheral nervous system. It is found throughout the length of the intestines and is responsible for normal bowel motility. Thus, abnormal development of the ENS is the main cause of gut motility disorders such as aganglionic megacolon. This lethal condition is caused by the absence of an intact ENS in the terminal regions of the gut; the affected segment stays contracted leading to intestinal obstruction, dilation and severe constipation. Human clinical cases and animal models have led to the identification of several genes important for ENS development. Nevertheless, given the complexity of the ENS, our understanding of its formation is far from complete. In order to identify new genes/loci important for ENS development, I have performed an insertional mutation screens in transgenic mice. Due to random insertion of transgenes in the mouse genome, this screen allowed the identification of three lines of mice, named "Dapple", "Dominant Spot" and "Holstein" that display an aganglionic megacolon phenotype. Genetic studies to date have shown that at least the mutations for Dapple and Dominant Spot are in new genes/loci. The proposed research program is aimed at identifying and characterizing the genes affected by these mutations with a special focus on the Dapple line. Molecular studies to date suggest that reduced expression of the new gene Kiaa1279 is responsible of the Dapple megacolon phenotype. In this regard, I now propose studies to understand the function of the Kiaa1279 gene product in ENS development. Overall, this research program will significantly expand the current limited knowledge of ENS development at the genetic, molecular and cellular levels. This new knowledge will represent key contributions to an important research field which is currently understudied in Canada.