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Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development

Abstract

Receptor tyrosine kinases often have critical roles in particular cell lineages by initiating signalling cascades in those lineages. Examples include the neural-specific TRK receptors1, the VEGF and angiopoietin endothelial-specific receptors2,3,4,5,6,7,8, and the muscle-specific MUSK receptor9,10,11. Many lineage-restricted receptor tyrosine kinases were initially identified as ‘orphans’ homologous to known receptors, and only subsequently used to identify their unknown growth factors. Some receptor-tyrosine-kinase–like orphans still lack identified ligands as well as biological roles. Here we characterize one such orphan, encoded by Ror2 (ref. 12). We report that disruption of mouse Ror2 leads to profound skeletal abnormalities, with essentially all endochondrally derived bones foreshortened or misshapen, albeit to differing degrees. Further, we find that Ror2 is selectively expressed in the chondrocytes of all developing cartilage anlagen, where it essential during initial growth and patterning, as well as subsequently in the proliferating chondrocytes of mature growth plates, where it is required for normal expansion. Thus, Ror2 encodes a receptor-like tyrosine kinase that is selectively expressed in, and particularly important for, the chondrocyte lineage.

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Figure 1: Disruption of the endogenous Ror2 allele, resulting in the encoding of a novel product in which the ecto- and transmembrane-domains of Ror2 are fused to lacZ (which replaces the normal tyrosine kinase-like cytodomain).
Figure 2: Ror2 is expressed in chondrocytes of early cartilaginous anlagen in embryos, as well as in chondrocytes of articular cartilage and growth plates in the adult.
Figure 3: Disruption of Ror2 results in widespread skeletal abnormalities (in bones formed by endochondral but not intramembranous ossification), although distal long bones in limb are more affected than proximal long bones.
Figure 4: Developmental progression of abnormalities in cartilaginous anlagen of Ror2−/− mice.
Figure 5: Schematic comparison between forelimb long bones in normal and Ror2−/− embryos at E17.5.

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Acknowledgements

We thank P.R. Vagelos, L.S. Schleifer and the rest of the Regeneron community for their support of this work; M.V. Simmons and L. Esau for mouse breeding and genotyping; L. Boccone, A. Lucarelli, J. Vercollone, X. Liu and D. Wu for technical assistance; F. Martin and S. Zabskie for in situ hybridizations; N. Gale for helpful discussions about embryo staining; C. Hartmann and C. Tabin for discussions and preliminary data; A. Boulet and M. Capecchi for noticing the similarity to the Prx mutants; and M. Oldridge and A. Wilkie for sharing collaborative data before publication.

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Correspondence to George D. Yancopoulos.

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DeChiara, T., Kimble, R., Poueymirou, W. et al. Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nat Genet 24, 271–274 (2000). https://doi.org/10.1038/73488

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