The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation.

Abstract

The winged helix transcription factor Fkh6 is expressed in the mesoderm of the gastrointestinal tract directly adjacent to the endoderm-derived epithelium. Homozygous null mice for Fkh6 showed postnatal growth retardation secondary to severe structural abnormalities of the stomach, duodenum, and jejunum. Dysregulation of epithelial cell proliferation in these organs resulted in an approximately fourfold increase in the 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 intestinal epithelia also suggests that epithelial cell-lineage allocation or differentiation may be affected by loss of Fkh6. From the analysis of a number of potential signaling molecules, we found Bmp2 and Bmp4 expression reduced in the gastrointestinal tract of Fkh6 mutant mice, suggesting that Fkh6 directs a signaling cascade that mediates communication between the mesenchyme and endoderm of the gut to regulate cell proliferation.

Cellular and molecular partners involved in gut morphogenesis and differentiation

“…These results can be related to two recent papers (Hentsch et al 1996;Kaestner et al 1997) that report the expression in the intestinal mesenchyme of the homeobox gene Hlx and the transcription factor Fkh6, and their ability to regulate the mitogenic signal of the visceral endoderm during development. Indeed, targeted disruption of Hlx genes is associated with a de¢cient gut elongation and looping, while disruption of Fkh6 is associated with expanded, branched crypts and lengthening of the villi with an overall altered architecture and cytodi¡erentiation.…”

“…Thus, these two regulatory genes appear, respectively, to control positively and negatively the epithelial cell proliferation. According to Kaestner et al (1997), BMP2 and BMP4 (bone morphogenetic proteins, which are members of the TGFb family) could be the targets of Fkh6, that are implicated in the signalling pathway from the mesenchyme to the epithelium. Moreover, it is worth noting that TGFb produced by ¢broblasts induce T84 cells, derived from a colon carcinoma lung metastasis, to form organized luminal structures composed of polarized cells (Halttunen et al 1996).…”

Foxl1 promotes liver repair following cholestatic injury in mice

“…12 The mice were maintained on a C57Bl/6J background. Genotyping was performed using the following primers and polymerase chain reaction (PCR) conditions: Foxl1 5 0 -CGCGTCGAGCCCCCGCAGAAG; and Foxl1 3 0 -CC CCTTCTCACGTG-GCACCTTC; and LacZ CGCCATTCGCC ATTCAGGCTGC.…”

“…Foxl1 À/À mice do not exhibit any baseline liver abnormalities indicating that Foxl1 is dispensable for liver development. 10,12 The livers of these mice, however, develop increasing necrosis at late time points after BDL, associated with reduced cholangiocyte and hepatocyte proliferation, and decreased expansion of bile ductular mass. The reduced expression of Wnt3a, Wnt7b and the Wnt target gene Cyclin D1 in Foxl1 mutants places Foxl1 as an upstream mediator of b-catenin-induced cholangiocyte proliferation.…”

Biological effects of FoxJ2 over-expression

“…However, some Fork Head factors exhibit remarkably constrained patterns in particular cases, such as at particular moments in development (Choi et al 2006). The role played by these transcription factors is important for various biological processes such as signal transduction (Tan et al 1998;Zhou et al 1998), cell differentiation (Kaestner et al 1997;Kume et al 1998), or even controlling longevity (Lin et al 1997;Ogg et al 1997).…”