Foxl1 controls the Wnt/beta-catenin pathway by modulating the expression of proteoglycans in the gut.

Foxl1 is a winged helix transcription factor expressed in the mesenchyme of the gastrointestinal tract. Foxl1 null mice display severe structural defects in the epithelia of the stomach, duodenum, and jejunum. Here we addressed the molecular mechanisms by which Foxl1 controls gastrointestinal differentiation. First we showed that the abnormalities found in the epithelia of the null mice are the result of an increase in the number of proliferating cells and not a change in the rate of cell migration. Next we investigated the regulatory circuits affected by Foxl1. We focused on the Wnt/beta-catenin signaling pathway as a possible target of Foxl1 as it has been shown to play a central role in gastrointestinal proliferation. We demonstrated that Foxl1 activates the Wnt/beta-catenin pathway by increasing extracellular proteoglycans, which act as co-receptors for Wnt. Thus we establish that Foxl1 is involved in the regulation of the Wnt/beta-catenin pathway, providing a novel link in mesenchymal/epithelial cross-talk in the gut. Moreover, we provide the first example implicating proteoglycans in the regulation of cellular proliferation in the gastrointestinal tract.