Targeted Disruption of the Wnt Regulator Kremen Induces Limb Defects and High Bone Density | Zendy

Kristina Ellwanger | Zendy; Hiroaki Saito | Zendy; Philippe Clément-Lacroix | Zendy; Nicole Maltry | Zendy; Joachim Niedermeyer | Zendy; Woon Kyu Lee | Zendy; Roland Baron | Zendy; Georges Rawadi | Zendy; Heiner Westphal | Zendy; Christof Niehrs | Zendy

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Targeted Disruption of the Wnt Regulator Kremen Induces Limb Defects and High Bone Density

Author(s) -

Kristina Ellwanger,

Hiroaki Saito,

Philippe Clément-Lacroix,

Nicole Maltry,

Joachim Niedermeyer,

Woon Kyu Lee,

Roland Baron,

Georges Rawadi,

Heiner Westphal,

Christof Niehrs

Publication year - 2008

Publication title -

molecular and cellular biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.14

H-Index - 327

eISSN - 1067-8824

pISSN - 0270-7306

DOI - 10.1128/mcb.00222-08

Subject(s) - wnt signaling pathway , dkk1 , biology , mutant , microbiology and biotechnology , bone morphogenetic protein , lrp5 , beta catenin , lrp6 , signal transduction , genetics , gene

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.

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