FoxF genes in development and disease

Abstract

Forkhead transcription factors of the FoxF group are important during embryonic de-velopment, and mutation of either of the members, Foxf1 and Foxf2, has fatal conse-quences. In this thesis, I present our recent findings about the mechanism of action of FoxF genes in development and disease. Haploinsufficiency for FOXF1 in humans causes alveolar capillary dysplasia with mis-alignment of pulmonary veins (ACDMPV), a rare lethal congenital disorder with incom-plete penetrance. We report a new ACDMPV case and define the genomic rearrangement which consists of a pericentric inversion on chromosome 16 (p11.2q24.1), which dis-rupts the FOXF1 5’-flanking region 134 kb upstream of the first exon. We further use this information in combination with chromatin modification data from the ENCODE data set to predict the extent of the FOXF1 regulatory domain and the critical genomic regions for ACDMPV. Gastrointestinal cancer, which is the result of uncontrolled proliferation of intestinal stem cells, is one of the most prevalent causes of death in the West. We show that Foxf2 regulates the number of intestinal stem cells and the proliferation rate in adult mouse intestine, with consequences for initiation and growth of intestinal tumors. Foxf2 limits the size of the stem cell niche by activating the expression of the extracellular Wnt inhib-itor Sfrp1 in mesenchymal cells surrounding the crypts of Lieberkühn. During this work we also developed a novel method for separation of intact intestinal epithelium from mesenchyme. Cleft palate is a common congenital malformation, associated with many genetic al-terations and environmental teratogens. Loss of Foxf2 results in cleft palate in mouse. We found that the cleft palate is the result of reduced proliferation and decreased extra-cellular matrix production in the neural crest-derived palatal shelf mesenchyme at a critical stage of palatal formation. The mechanistic basis appears to be a diminished Tgfβ signaling, and decreased expression of integrins required for activation of latent Tgfβ.