title: Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density.
abstract: Kremen1 and Kremen2 (Krm1 and Krm2) are transmembrane coreceptors for Dickkopf1 (Dkk1), an antagonist of Wnt/beta-catenin signaling. The physiological relevance of Kremen proteins in mammals as Wnt modulators is unresolved. We generated and characterized Krm mutant mice and found that double mutants show enhanced Wnt signaling accompanied by ectopic postaxial forelimb digits and expanded apical ectodermal ridges. Triple mutant Krm1(-/-) Krm2(-/-) Dkk1(+/-) mice show enhanced growth of ectopic digits, indicating that Dkk1 and Krm genes genetically interact during limb development. Wnt/beta-catenin signaling also plays a critical role in bone formation. Single Krm mutants show normal bone formation and bone mass, while double mutants show increased bone volume and bone formation parameters. Our study provides the first genetic evidence for a functional interaction of Kremen proteins with Dkk1 as negative regulators of Wnt/beta-catenin signaling and reveals that Kremen proteins are not universally required for Dkk1 function.
authors.affiliation: Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Ellwanger
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.forename: Philippe
authors.initials: P
authors.lastname: Clément-Lacroix
authors.forename: Nicole
authors.initials: N
authors.lastname: Maltry
authors.forename: Joachim
authors.initials: J
authors.lastname: Niedermeyer
authors.forename: Woon Kyu
authors.initials: WK
authors.lastname: Lee
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.forename: Georges
authors.initials: G
authors.lastname: Rawadi
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
mesh_terms: D000818:Animals; D019521:Body Patterning; D015519:Bone Density / Q000235:genetics*; D002460:Cell Line; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D005121:Extremities / Q000196:embryology / Q000473:pathology; D005298:Fertility; D017353:Gene Deletion; D018390:Gene Targeting; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010012:Osteogenesis; D011485:Protein Binding; D015398:Signal Transduction; D019699:Thrombospondins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019699:Thrombospondins; D051153:Wnt Proteins; C501127:Dkk1 protein, mouse; C486077:Kremen1 protein, mouse; C518903:RSPO1 protein, mouse