title: Lrp5 and Lrp6 play compensatory roles in mouse intestinal development.
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.
authors.affiliation: Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhong
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Baker
authors.forename: Cassandra R
authors.initials: CR
authors.lastname: Zylstra-Diegel
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007422:Intestines / Q000196:embryology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017384:Sequence Deletion / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D019938:Cyclin D1