The mechanisms controlling establishment and maintenance of enterocytes with the capacity to accomplish regionally specific functions are unclear. The long-term goal of our laboratory is to define the regulators and pathways required to create this functional specificity in the intestine and ultimately to manipulate these pathways to control function. Our preliminary studies have shown that loss of the zinc finger transcription factor GATA4 in the jejunum compromises jejunal identity and function suggesting that GATA4 plays a dominant role in conferring jejunal identity. Therefore, the central hypothesis driving this proposal is that restriction of GATA4 along the anterior-posterior axis of the small intestine is required to confer regional specificity to the intestinal epithelium. We propose in Aim 1 to identify the timing of GATA4 restriction along the anterior-posterior axis of the small intestinal epithelium and the extent to which such restriction corresponds with the activation of the jejunal-specific gene expression program. Our studies in Aim 2 will define the mechanisms controlling the restriction of GATA4 along the anterior-posterior axis of the small intestinal epithelium. To determine if GATA4 is sufficient to confer jejunal fate in the intestine, we will ectopically express GATA4 in the ileum, a site where GATA4 is normally absent (Aim 3). Completion of the proposed studies is expected to elucidate the mechanism through which an individual transcription factor acts to regulate regional identity in the intestine. This is significant because these studies will provide knowledge into the basic processes governing the determination of the functional fate of the intestinal epithelium, a prerequisite to the development of novel therapies to combat intestinal failure

Public Health Relevance

The goal of the current proposal is to determine how restricted expression of the transcription factor GATA4 in the small intestine controls the establishment and maintenance of functional regionalization in the intestine. Completion of the proposed studies will provide knowledge into the basic processes that govern delineation of the duodenum, jejunum, and ileum, a process that is not yet understood. Such insight has the potential to lead to the development of novel therapies to combat intestinal failure such as the ability to use pharmaceuticals to restore lost functions to intestinal tissue and to engineer intestinal tissue in vitro for transplantation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Carrington, Jill L
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Thompson, Cayla A; DeLaForest, Ann; Battle, Michele A (2018) Patterning the gastrointestinal epithelium to confer regional-specific functions. Dev Biol 435:97-108
Thompson, Cayla A; Wojta, Kevin; Pulakanti, Kirthi et al. (2017) GATA4 Is Sufficient to Establish Jejunal Versus Ileal Identity in the Small Intestine. Cell Mol Gastroenterol Hepatol 3:422-446
Chin, Alana M; Tsai, Yu-Hwai; Finkbeiner, Stacy R et al. (2016) A Dynamic WNT/?-CATENIN Signaling Environment Leads to WNT-Independent and WNT-Dependent Proliferation of Embryonic Intestinal Progenitor Cells. Stem Cell Reports 7:826-839
Kohlnhofer, Bridget M; Thompson, Cayla A; Walker, Emily M et al. (2016) GATA4 regulates epithelial cell proliferation to control intestinal growth and development in mice. Cell Mol Gastroenterol Hepatol 2:189-209
Moore, Benjamin D; Jin, Ramon U; Lo, Heiyong et al. (2016) Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4? (HNF4?) Is Vital to Beta-cell Function. J Biol Chem 291:6146-57
Walker, Emily M; Thompson, Cayla A; Battle, Michele A (2014) GATA4 and GATA6 regulate intestinal epithelial cytodifferentiation during development. Dev Biol 392:283-94
Walker, Emily M; Thompson, Cayla A; Kohlnhofer, Bridget M et al. (2014) Characterization of the developing small intestine in the absence of either GATA4 or GATA6. BMC Res Notes 7:902
Patankar, Jay V; Obrowsky, Sascha; Doddapattar, Prakash et al. (2012) Intestinal GATA4 deficiency protects from diet-induced hepatic steatosis. J Hepatol 57:1061-8
Bondow, Benjamin J; Faber, Mary L; Wojta, Kevin J et al. (2012) E-cadherin is required for intestinal morphogenesis in the mouse. Dev Biol 371:1-12
Xuan, Shouhong; Borok, Matthew J; Decker, Kimberly J et al. (2012) Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest 122:3516-28

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