Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo

• Published in: Developmental biology 2011-11, Vol.359 (2), p.222-229
• Main Authors: Joeng, Kyu Sang, Schumacher, Cassie A., Zylstra-Diegel, Cassandra R., Long, Fanxin, Williams, Bart O.
• Format: Article
• Language: English
• Subjects: adherens junctions; Animals; beta Catenin - genetics; Body Patterning - genetics; Bone and Bones - embryology; Bone and Bones - metabolism; Bone Development - genetics; Cartilage; Cartilage - embryology; Cartilage - metabolism; Chondrocyte; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryogenesis; Embryos; Extremities - embryology; Female; Gene Expression Regulation, Developmental; In Situ Hybridization; Limbs; Low Density Lipoprotein Receptor-Related Protein-5 - genetics; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Lrp5; LRP5 protein; Lrp6; Male; Mesenchyme; Mesoderm - embryology; Mesoderm - metabolism; Mice; Mice, Knockout; Mouse; mutants; Osteoblast; Osteoblastogenesis; Osteoblasts; Osteogenesis - genetics; Pattern formation; phenotype; receptors; Signal Transduction - genetics; skeletal development; Supernumerary; Time Factors; Wnt; Wnt protein; α-catenin; β-catenin
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2011.08.020

The role of Wnt signaling in osteoblastogenesis in the embryo remains to be fully established. Although β-catenin, a multifunctional protein also mediating canonical Wnt signaling, is indispensable for embryonic osteoblast differentiation, the roles of the key Wnt co-receptors Lrp5 and Lrp6 are unclear. Indeed, global deletion of either Lrp5 or Lrp6 did not overtly affect osteoblast differentiation in the mouse embryo. Here, we generated mice lacking both receptors specifically in the embryonic mesenchyme and observed an absence of osteoblasts in the embryo. In addition, the double-deficient embryos developed supernumerary cartilage elements in the zeugopod, revealing an important role for mesenchymal Lrp5/6 signaling in limb patterning. Importantly, the phenotypes of the Lrp5/6 mutant closely resembled those of the β-catenin-deficient embryos. These phenotypes are likely independent of any effect on the adherens junction, as deletion of α-catenin, another component of the complex, did not cause similar defects. Thus, Lrp5 and 6 redundantly control embryonic skeletal development, likely through β-catenin signaling. ► Single deletion of either Lrp5 or Lrp6 had little effect on embryonic skeleton. ► Double deletion of Lrp5 and Lrp6 in limb mesenchyme phenocopied β-catenin deletion. ► Deletion of α-catenin in limb mesenchyme had little effect on skeletal development.