Lrp5 and Lrp6 Play Compensatory Roles in Mouse Intestinal Development

J Cell Biochem. 2012 Jan;113(1):31-8. doi: 10.1002/jcb.23324.

Abstract

Low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5 and Lrp6) are co-receptors of Wnt ligands and play important roles in Wnt/β-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 Lrp5(gut-/-) mice was normal. In addition, mice homozygous for villin-Cre-induced deletion of Lrp6 (Lrp6(gut-/-)) were viable with apparently normal intestinal differentiation and function. However, mice homozygous for villin-Cre inactivated alleles of both genes (Lrp5(gut-/-) ; Lrp6(gut-/-)) died within 1 day of birth. Analysis of embryonic Lrp5(gut-/-); Lrp6(gut-/-) 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/β-catenin target, cyclin D1, was specifically reduced in the intestinal epithelium of Lrp5(gut-/-); Lrp6(gut-/-) 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/β-catenin signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cyclin D1 / metabolism
  • Gene Expression Regulation, Developmental
  • Intestines / embryology*
  • Low Density Lipoprotein Receptor-Related Protein-5 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Mice
  • Sequence Deletion / genetics
  • Wnt Signaling Pathway / genetics*

Substances

  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp5 protein, mouse
  • Lrp6 protein, mouse
  • Cyclin D1