Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density

被引：83

作者：

Ellwanger, Kristina ^{[1
]}

Saito, Hiroaki ^{[2
,3
]}

Clement-Lacroix, Philippe ^{[4
]}

Maltry, Nicole ^{[1
]}

Niedermeyer, Joachim ^{[1
]}

Lee, Woon Kyu ^{[5
]}

Baron, Roland ^{[2
,3
]}

Rawadi, Georges ^{[4
]}

Westphal, Heiner ^{[5
]}

Niehrs, Christof ^{[1
]}

机构：

[1] Deutsch Krebsforschungszentrum, Div Mol Embryol, DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA

[4] Galapagos Co, Romainville, France

[5] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2008年 / 28卷 / 15期

关键词：

D O I：

10.1128/MCB.00222-08

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Writ 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(-1-) 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.

引用

页码：4875 / 4882

页数：8

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