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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Barbacid, M. Neurotrophic factors and their receptors. Curr. Opin. Cell. Biol. 7, 148–155 (1995).
Dumont, D.J. et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909 (1994).
Sato, T.N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).
Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).
Suri, C. et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).
Maisonpierre, P.C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
Ferrara, N. Vascular endothelial growth factor: molecular and biological aspects. Curr. Top. Microbiol. Immunol. 237, 1–30 (1999).
Eriksson, U. & Alitalo, K. Structure, expression and receptor-binding properties of novel vascular endothelial growth factors. Curr. Top. Microbiol. Immunol. 237, 41–57 (1999).
Valenzuela, D.M. et al. Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15, 573–584 (1995).
DeChiara, T.M. et al. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85, 501–512 (1996).
Glass, D.J. et al. Agrin acts via a MuSK receptor complex. Cell 85, 513–523 (1996).
Masiakowski, P. & Carroll, R.D. A novel family of cell surface receptors with tyrosine kinase-like domain. J. Biol. Chem. 267, 26181–26190 (1992).
Oldridge, M. et al. Dominant mutations in ROR2, encoding the orphan receptor tyrosine kinase, cause brachydactyly type B. Nature Genet. 24, 275–278 (2000)
Davis, A.P., Witte, D.P., Hsieh-Li, H.M., Potter, S.S. & Capecchi, M.R. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature 375, 791–795 (1995).
ten Berge, D., Brouwer, A., Korving, J., Martin, J.F. & Meijlink, F. Prx1 and Prx2 in skeletogenesis: roles in the craniofacial region, inner ear and limbs. Development 125, 3831–3842 (1998).
Karaplis, A.C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8, 277–289 (1994).
Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666 (1996).
Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996).
Weir, E.C. et al. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc. Natl Acad. Sci. USA 93, 10240–10245 (1996).
Schipani, E. et al. Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide. Proc. Natl Acad. Sci. USA 94, 13689–13694 (1997).
Muenke, M. & Schell, U. Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet. 11, 308–313 (1995).
Wilkie, A.O., Morriss-Kay, G.M., Jones, E.Y. & Heath, J.K. Functions of fibroblast growth factors and their receptors. Curr. Biol. 5, 500–507 (1995).
Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921 (1996).
Colvin, J.S., Bohne, B.A., Harding, G.W., McEwen, D.G. & Ornitz, D.M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).
Naski, M.C., Colvin, J.S., Coffin, J.D. & Ornitz, D.M. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125, 4977–4988 (1998).
DeChiara, T.M. et al. Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 83, 313–322 (1995).
Conover, J.C. et al. Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature 375, 235–238 (1995).
McLeod, M.J. Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizaren red S. Teratology 22, 299–301 (1980).
Mercer, E.H., Hoyle, G.W., Kapur, R.P., Brinster, R. & Palmiter, R.D. The dopamine b-hydroxylase gene promoter directs expression of E. coli lacZ to sympathetic and other neurons in adult transgenic mice. Neuron 7, 703–716 (1991).
Vanky, P., Brockstedt, U., Hjerpe, A. & Wikstrom, B. Kinetic studies on epiphyseal growth cartilage in the normal mouse. Bone 22, 331–339 (1998).
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/73488
This article is cited by
-
Correlates of estimated lifetime cruciate ligament survival inform potential rupture risk reduction strategies: findings from the Exceptional Aging in Rottweilers Study
Scientific Reports (2023)
-
Loss of signal transducer and activator of transcription 3 impaired the osteogenesis of mesenchymal progenitor cells in vivo and in vitro
Cell & Bioscience (2021)
-
Molecular, functional, and gene expression analysis of zebrafish Ror1 receptor
Fish Physiology and Biochemistry (2019)
-
Multivariate genome-wide association analysis identifies novel and relevant variants associated with anterior cruciate ligament rupture risk in the dog model
BMC Genetics (2018)
-
Ror2-mediated alternative Wnt signaling regulates cell fate and adhesion during mammary tumor progression
Oncogene (2017)