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Molecular and Cellular Biology, August 2008, p. 4875-4882, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.00222-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Kristina Ellwanger,¹ Hiroaki Saito,² Philippe Clément-Lacroix,³ Nicole Maltry,¹ Joachim Niedermeyer,¹ Woon Kyu Lee,^4, Roland Baron,² Georges Rawadi,³ Heiner Westphal,⁴ and Christof Niehrs^1*

Division of Molecular Embryology, Deutsches Krebsforschungszentrum, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany,¹ Harvard University, School of Medicine and School of Dental Medicine, Boston, Massachusetts 02115,² Galapagos Company, Romainville, France,³ Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-2790⁴

Received 11 February 2008/ Returned for modification 1 April 2008/ Accepted 19 May 2008

Kremen1 and Kremen2 (Krm1 and Krm2) are transmembrane coreceptors for Dickkopf1 (Dkk1), an antagonist of Wnt/β-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/β-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/β-catenin signaling and reveals that Kremen proteins are not universally required for Dkk1 function.

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* Corresponding author. Mailing address: Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 49-6221-42-4690. Fax: 49-6221-42-4692. E-mail: niehrs{at}dkfz.de

Published ahead of print on 27 May 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Laboratory Animal Medicine, College of Medicine, Yonsei University, 134 Sinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea.

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Molecular and Cellular Biology, August 2008, p. 4875-4882, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.00222-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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