http://repub.eur.nl/res/aut/17206/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/14795/ 2008-10-01T00:00:00Z GATA4, a transcription factor expressed in the proximal small intestine but not in the distal ileum, maintains proximal-distal distinctions by multiple processes involving gene repression, gene activation, and cell fate determination. Friend of GATA (FOG) is an evolutionarily conserved family of cofactors whose members physically associate with GATA factors and mediate GATA-regulated repression in multiple tissues. Using a novel, inducible, intestine-specific Gata4 knock-in model in mice, in which wild-type GATA4 is specifically inactivated in the small intestine, but a GATA4 mutant that does not bind FOG cofactors (GATA4ki) continues to be expressed, we found that ileal-specific genes were significantly induced in the proximal small intestine (P < 0.01); in contrast, genes restricted to proximal small intestine and cell lineage markers were unaffected, indicating that GATA4-FOG interactions contribute specifically to the repression function of GATA4 within this organ. Fog1 mRNA displayed a proximal-distal pattern that parallels that of Gata4, and FOG1 protein was co-expressed with GATA4 in intestinal epithelial cells, implicating FOG1 as the likely mediator of GATA4 function in the small intestine. Our data are the first to indicate FOG function and expression in the mammalian small intestine. http://repub.eur.nl/res/pub/17334/ 2006-11-29T00:00:00Z The mammalian small intestine is responsible for the terminal digestion and absorption of nutrients, water homeostasis, and the elimination of waste products, which in turn, are essential processes for life. These processes however, are easily disrupted by infection, inflammatory processes such as Crohn’s disease, cancer, and resection. The small intestine is equipped with specific proteins, such as enzymes to digest nutrients (digestion) and ‘transporters’ to carry the nutrients into the body (absorption). These tools for digestion and absorption are specifically expressed in the enterocytes of the small intestine and this expression is regulated by a complex of regulatory proteins among which intestinal transcription factors. These regulatory proteins are proposed to be important for intestinal gene expression, differentiation and development and are central to intestinal function. A better insight into the role that specific transcription factors play in these processes will thus complement our understanding of the regulation of intestinal function. Such fundamental knowledge will provide critical insight into disease processes and repair mechanisms of the intestinal epithelium, and identify potential avenues of intervention to correct lost or deficient intestinal function. The research described in this thesis investigates the role of the transcription factors Gata4 and Hnf1< in intestinal gene expression in vivo.