Reciprocal Signaling in Gastrointestinal Tract Development

超过10%的美国人口患有胃肠道（GI）疾病。互反信号 在胃肠道组分中，包括肠上皮、肠神经系统（ENS）和肠微生物群 对胃肠道健康和体内平衡至关重要这种相互信号的破坏可能导致疾病 如炎症性肠病（IBD）。我们和其他人已经证明， 对肠道正常发育至关重要我们还确定了肠道微生物群在以下方面的一个先前未知的作用： 建立发育中的肠上皮和发育中的ENS的正常细胞组成： 在没有肠道微生物群的情况下，存在较少的肠道上皮分泌细胞和较多的ENS神经胶质。这些 发育缺陷与Notch途径突变体中所见的发育缺陷完全相反。我们 观察激发了这样的假设，即肠道微生物群影响发育细胞的命运决定， 肠上皮细胞和ENS通过抑制Notch信号传导。我们提出3个目标来解决这个假设：1）我们 将使用遗传镶嵌来测试Notch信号是否是肠上皮自主需要的， ENS来指定这些组织中的每一个中的细胞命运决定。2)我们将操纵宿主基因功能， 微生物协会，以测试微生物群是否影响肠上皮和ENS中的细胞命运， 抑制Notch信号传导。3)我们将鉴定指定ENS和肠上皮细胞命运的基因， 它们是否在微生物调节的途径中起作用。这些实验将揭示机制， Notch信号传导影响肠上皮和ENS中发育细胞的命运决定， 微生物群会影响该途径中的哪些步骤。因为肠道上皮细胞处于 不断更新，了解这些发展决定的性质将对 了解肠道中细胞一生的命运决定。我们的研究将提供更多 完整了解促进肠道发育和健康的分子机制，知识 这是迫切需要的，以设计更好的诊断和治疗衰弱，有时致命的肠道 疾病如IBD。

Over 10% of the US population suffers from gastrointestinal (Gl) tract disorders. Reciprocal signaling among Gl tract components, including the gut epithelium, enteric nervous system (ENS), and gut microbiota are crucial for Gl tract health and homeostasis. Disruption of this reciprocal signaling can result in diseases such as inflammatory bowel disease (IBD). We and others have shown that the resident microbiota are crucial for normal gut development. We have also identified a previously unknown role for gut microbiota in establishing the normal cellular composition of both the developing gut epithelium and the developing ENS: in the absence of gut microbiota, there are fewer gut epithelium secretory cells and more ENS glia. These developmental defects are exactly opposite to developmental defects seen in Notch pathway mutants. Our observations motivate the hypothesis that gut microbiota influence developmental cell fate decisions in the gut epithelium and ENS by inhibiting Notch signaling. We propose 3 Aims to address this hypothesis: 1) We will use genetic mosaics to test whether Notch signaling is required autonomously in the gut epithelium and the ENS to specify cell fate decisions in each of these tissues. 2) We will manipulate host gene function and microbial associations to test whether the microbiota affect cell fates in the gut epithelium and ENS by repressing Notch signaling. 3) We will identify genes that specify ENS and gut epithelium cell fates and test whether they function in microbially-regulated pathways. These experiments will reveal the mechanisms by which Notch signaling affects developmental cell fate decisions in the gut epithelium and ENS and identify which steps in the pathway are affected by the microbiota. Because the gut epithelium is in a state of constant renewal, learning the nature of these developmental decisions will have important ramifications for understanding cell fate decisions in the gut throughout life. Together our studies will provide a more complete understanding of the molecular mechanisms that promote gut development and health, knowledge that is urgently needed to design better diagnostics and therapies for debilitating and sometimes fatal gut diseases such as IBD.