Abnormal development of gastrointestinal system of homozygous Foxp2(R552H)-mutated mice

Forkhead box protein P2 (Foxp2) regulates the expression of genes related to organ morphogenesis. Homozygous Foxp2(R552H) knock-in (Foxp2^R552H/R552H) mice exhibit abnormal brain development, and die around the weaning period. Here we demonstrate that Foxp2^R552H/R552H mice exhibit abnormal development of gastrointestinal (GI) system, followed by atrophy of stomach, abnormal rotation of intestine, and decreased expression of genes related to GI system development such as bar-like home box 1 (BARX1) and secreted frizzled-related protein 1 (Sfrp1), antagonist for Wnt/β-catenin signaling, and decreased expression of E-cadherin and Zonula occludens-1 (ZO-1) in epithelium, followed with increase of Zonulin in the serum, marker of leaky gut, and decrease of alpha-smooth muscle actin (SMA) in smooth muscle, resulting in their atrophy. Foxp2^+/+ and Foxp2^R552H/R552H transgenic mice expressing Foxp2 promoter-mediated mCherry exhibit that Foxp2 autoregulates its expression in the developing stomach. Foxp2 may control Wnt/β-catenin signaling via its autoregulation system, but Foxp2(R552H) may not. Our results suggest that Foxp2 is necessary for the development of the GI system.