Reciprocal Signaling in Gastrointestinal Tract Development

超过10%的美国人口患有胃肠道疾病。互惠信令 在胃肠道成分中，包括肠道上皮、肠道神经系统(ENS)和肠道微生物区系 对胆道健康和动态平衡至关重要。这种相互作用的信号的中断可能导致疾病 例如炎症性肠病(IBD)。我们和其他人已经证明了栖息的微生物群是 对正常的肠道发育至关重要。我们还确定了肠道微生物区系以前未知的作用 建立发育中的肠道上皮和发育中的ENS的正常细胞组成： 在没有肠道微生物区系的情况下，肠上皮分泌细胞较少，神经胶质细胞较多。这些 发育缺陷与Notch途径突变体中的发育缺陷正好相反。我们的 观察结果支持这样的假设，即肠道微生物区系影响发育细胞命运的决定 肠上皮细胞和ENS通过抑制Notch信号。我们提出3个目标来解决这一假设：1)我们 将使用遗传马赛克来测试肠上皮和肠上皮是否自主需要Notch信号 ENS指定这些组织中每一个组织的细胞命运决定。2)我们将操纵宿主基因功能和 微生物联合测试微生物区系是否通过以下方式影响肠道上皮和肠上皮细胞的命运 抑制Notch信令。3)我们将识别特定ENS和肠道上皮细胞命运的基因并进行测试 它们是否在微生物调控的途径中发挥作用。这些实验将通过以下方式揭示这些机制 哪种Notch信号影响肠上皮和ENS中发育细胞命运的决定和鉴定 途径中的哪些步骤会受到微生物区系的影响。因为肠道上皮处于一种 不断更新，了解这些发展决策的性质将对以下方面产生重要影响 了解一生中肠道中细胞命运的决定。我们的研究将共同为我们提供更多 完全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虚弱，有时甚至致命的肠道 IBD等疾病。

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.