MISEXPRESSION OF THE PANCREATIC HOMEODOMAIN PROTEIN IDX-1 BY THE HOXA-4 PROMOTER ASSOCIATED WITH AGENESIS OF THE CECUM

Background & Aims: The endoderm-specific homeodomain transcription fac tor IDX-1 is critical for pancreas development and for the regulation of islet cell-specific genes. During development, IDX-1 is expressed i n the epithelial cells of the endoderm in the pancreatic anlage of the foregut. The aim of this study was to determine whether IDX-1 may hav e potential properties of a master homeotic determinant of pancreas an d/or gut development. Methods: Transgenic mice were generated in which the expression of IDX-1 was misdirected by a promoter of the mesoderm -specific homeodomain protein Hoxa-4 known to express in the stomach a nd hindgut during development. The expectation was the formation of ec topic pancreatic tissue or alterations of gut patterning or morphology . Results: Although no ectopic induction of pancreatic markers was fou nd in these transgenic mice, they manifested an altered midgut-hindgut union and agenesis of the cecum. Further, IDX-1 binds to the gut-spec ific homeodomain protein Cdx-2 and inhibits transactivation of the suc rase-isomaltase promoter by Cdx-2. Conclusions: These findings further support the emerging understanding that interactions among different classes of homeodomain proteins, expressed in a spatially and temporal ly restricted manner during development, determine the pattern of orga nogenesis. A possible mechanism for the dysmorphogenesis of the proxim al colon may be an inhibition of Cdx-2 actions by IDX-1.