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

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Kremen1 and Kremen2 (Krm1 and Krm2) are transmembrane coreceptors for Dickkopf1 (Dkk1), a known antagonist of Wnt/beta-catenin signaling.
• The precise physiological role of Kremen proteins in mammalian Wnt signaling modulation remains largely uncharacterized.

Purpose of the Study:

• To investigate the functional relevance of Kremen proteins in mammalian development and Wnt signaling.
• To elucidate the genetic interaction between Kremen proteins and Dickkopf1 (Dkk1) during limb development and bone formation.

Main Methods:

• Generation and characterization of Kremen (Krm) mutant mice, including double and triple mutants with Dkk1.
• Analysis of Wnt signaling pathway activity, limb morphology (digit development, apical ectodermal ridges), and bone formation parameters.

Main Results:

• Krm double mutant mice exhibited enhanced Wnt signaling, leading to ectopic postaxial forelimb digits and expanded apical ectodermal ridges.
• Triple mutant Krm1(-/-) Krm2(-/-) Dkk1(+/-) mice displayed accelerated growth of ectopic digits, confirming a genetic interaction between Dkk1 and Krm genes in limb development.
• While single Krm mutants had normal bone formation, Krm double mutants showed significantly increased bone volume and enhanced bone formation parameters.

Conclusions:

• This study provides the first genetic evidence for Kremen proteins acting as negative regulators of Wnt/beta-catenin signaling in conjunction with Dkk1.
• Kremen proteins are demonstrated to be crucial modulators of Wnt signaling during mammalian limb development and bone homeostasis.
• The findings suggest that Kremen proteins are not universally essential for all Dkk1 functions, highlighting context-dependent roles.