Lrp5 and Lrp6 play compensatory roles in mouse intestinal development

Low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5 and Lrp6) are co-receptors of Wnt ligands and play important roles in Wnt/beta-catenin signal transduction. Mice homozygous for a germline deletion of Lrp6 die at birth with several associated defects, while Lrp5-deficient mice are viable. Here, we conditionally deleted Lrp5 and/or Lrp6 in the mouse gut (gut-/-) by crossing mice carrying floxed alleles of Lrp5 and Lrp6 to a strain expressing Cre recombinase from the villin promoter (villin-Cre). The changes in morphology, differentiation, and Wnt signal transduction were validated using immunohistochemistry and other staining. Consistent with observations in mice carrying a homozygous germline deletion in Lrp5, intestinal development in Lrp5gut-/- mice was normal. In addition, mice homozygous for villin-Cre-induced deletion of Lrp6 (Lrp6gut-/-) were viable with apparently normal intestinal differentiation and function. However, mice homozygous for villin-Cre inactivated alleles of both genes (Lrp5gut-/-; Lrp6gut-/-) died within 1 day of birth. Analysis of embryonic Lrp5gut-/-; Lrp6gut-/- intestinal epithelium showed a progressive loss of cells, an absence of proliferation, and a premature differentiation of crypt stem/precursor cells; no notable change in differentiation was observed in the embryos lacking either gene alone. Further immunohistochemical studies showed that expression of the Wnt/beta-catenin target, cyclin D1, was specifically reduced in the intestinal epithelium of Lrp5gut-/-; Lrp6gut-/- embryos. Our data demonstrate that Lrp5 and Lrp6 play redundant roles in intestinal epithelium development, and that Lrp5/6 might regulate intestinal stem/precursor cell maintenance by regulating Wnt/beta-catenin signaling. J. Cell. Biochem. 113: 3138, 2012. (C) 2011 Wiley Periodicals, Inc.