THE MESENCHYMAL WINGED HELIX TRANSCRIPTION FACTOR FKH6 IS REQUIRED FOR THE CONTROL OF GASTROINTESTINAL PROLIFERATION AND DIFFERENTIATION

The winged helix transcription factor Fkh6 is expressed in the mesoder m of the gastrointestinal tract directly adjacent to the endoderm-deri ved epithelium. Homozygous null mice for Fkh6 showed postnatal growth retardation secondary to severe structural abnormalities of the stomac h, duodenum, and jejunum. Dysregulation of epithelial cell proliferati on in these organs resulted in an approximately fourfold increase in t he number of dividing intestinal epithelial cells and marked expansion of the proliferative zone. As a consequence, the tissue architecture of the stomach and small intestine was distorted, with abnormal crypt structure, formation of mucin filled cysts, and lengthening of villi. Changes in the cellular phenotype and composition of the gastric and i ntestinal epithelia also suggests that epithelial cell-lineage allocat ion or differentiation may be affected by loss of Fkh6. from the analy sis of a number of potential signaling molecules, we found Bmp2 and Bm p4 expression reduced in the gastrointestinal tract of Fkh6 mutant mic e, suggesting that Fkh6 directs a signaling cascade that mediates comm unication between the mesenchyme and endoderm of the gut to regulate c ell proliferation.