The gastrointestinal tract is a continuous tube that extends from the mouth to the anus. It is responsible for the passage of foodstuffs, the subsequent absorption of nutrients and water, and the transport of waste products from the body. The gut tube is made up of distinct tissue layers all of which contribute to gut function. The epithelium of the mucosal layer is where the absorption and transport of nutrients occurs. It also forms a barrier that protects against pathogen invasion but allows the selective transport of macromolecules. When the epithelium of the gut is damaged it can result in influx of pathogens and a severe inflammatory response that contributes to liver toxicity and a variety of gastrointestinal diseases including Crohn's disease and inflammatory bowel disease. Understanding how the intestinal epithelium is formed during embryogenesis and how it is maintained in the adult is, therefore, important for us to understand gut function and the processes that go awry in gastrointestinal disease. Here we propose that the transcription factors Hnf4, Gata4 and Gata6 have central roles in regulating the formation of the gut epithelium. To test whether this is true we have has used the Cre-LoxP system to generate mice harboring alleles of Hnf4 and Gata4 that can be deleted specifically in intestinal epithelial cells. We will use these mice to determine whether Gata4 is required for the earliest stages of intestinal epithelial cell differentiation and whether Hnf4 is essential for epithelial morphogenesis. In addition, we propose to generate Gata6- and Gata6; Gata4-doubly null embryos by tetraploid embryo complementation to determine the relative contribution of these two Gata factors toward early stages of gut development.
