The mammalian intestinal epithelial cells develop along 3 major axes: (1) the longitudinal duodenum-to-colon axis, (2) the vertical crypt-to-villus axis, and (3) the temporal axis during development. The process of differentiation into each of the components of these axes is dependent on a specific program of gene expression that is unique to that cell type and location. The investigator proposes the adenosine deaminase gene as a model system in which to investigate the network regulating gene expression along the various axes in the small intestine. He has shown that high levels of ADA mRNA are present in the duodenum where they are limited to the villus enterocytes. He has also provided preliminary evidence from transgenic mouse experiments that the duodenal-specific regulation of the ADA gene is located in an intragenic segment, probably in intron 2.
Three specific aims are proposed: (1) to characterize the duodenal-specific regulatory region within the ADA gene, including a putative duodenal-specific enhancer element, (2) to identify and characterize the duodenal-specific factors which bind to the enhancer element identified in (1), and (3) to identify and characterize the mouse ADA gene duodenal-specific regulatory element.
|Dusing, Mary R; Maier, Elizabeth A; Aronow, Bruce J et al. (2010) Onecut-2 knockout mice fail to thrive during early postnatal period and have altered patterns of gene expression in small intestine. Physiol Genomics 42:115-25|
|Maier, Elizabeth A; Dusing, Mary R; Wiginton, Dan A (2006) Temporal regulation of enhancer function in intestinal epithelium: a role for Onecut factors. J Biol Chem 281:32263-71|
|Dusing, Mary R; Wiginton, Dan A (2005) Epithelial lineages of the small intestine have unique patterns of GATA expression. J Mol Histol 36:15-24|
|Dusing, Mary R; Florence, Elizabeth A; Wiginton, Dan A (2003) High-level activation by a duodenum-specific enhancer requires functional GATA binding sites. Am J Physiol Gastrointest Liver Physiol 284:G1053-65|
|Bates, Michael D; Erwin, Christopher R; Sanford, L Philip et al. (2002) Novel genes and functional relationships in the adult mouse gastrointestinal tract identified by microarray analysis. Gastroenterology 122:1467-82|
|Dusing, M R; Florence, E A; Wiginton, D A (2001) Pdx-1 is required for activation in vivo from a duodenum-specific enhancer. J Biol Chem 276:14434-42|
|Dusing, M R; Brickner, A G; Lowe, S Y et al. (2000) A duodenum-specific enhancer regulates expression along three axes in the small intestine. Am J Physiol Gastrointest Liver Physiol 279:G1080-93|