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RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6

(2018) NATURE. 557(7706). p.564-569
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Abstract
The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling(1-3). Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs. Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers.
Keywords
APICAL ECTODERMAL RIDGE, R-SPONDIN, WNT/BETA-CATENIN, TETRA-AMELIA, WNT, RECEPTORS, STEM-CELLS, NULL MICE, R-SPONDIN2, LGR5, GROWTH

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Citation

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Chicago
Szenker-Ravi, Emmanuelle, Umut Altunoglu, Marc Leushacke, Celia Boss-Lefevre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, et al. 2018. “RSPO2 Inhibition of RNF43 and ZNRF3 Governs Limb Development Independently of LGR4/5/6.” Nature 557 (7706): 564–569.
APA
Szenker-Ravi, E., Altunoglu, U., Leushacke, M., Boss-Lefevre, C., Khatoo, M., Tran, H. T., Naert, T., et al. (2018). RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. NATURE, 557(7706), 564–569.
Vancouver
1.
Szenker-Ravi E, Altunoglu U, Leushacke M, Boss-Lefevre C, Khatoo M, Tran HT, et al. RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. NATURE. London: Nature Publishing Group; 2018;557(7706):564–9.
MLA
Szenker-Ravi, Emmanuelle, Umut Altunoglu, Marc Leushacke, et al. “RSPO2 Inhibition of RNF43 and ZNRF3 Governs Limb Development Independently of LGR4/5/6.” NATURE 557.7706 (2018): 564–569. Print.
@article{8565445,
  abstract     = {The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling(1-3). Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs. Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers.},
  author       = {Szenker-Ravi, Emmanuelle and Altunoglu, Umut and Leushacke, Marc and Boss-Lefevre, Celia and Khatoo, Muznah and Tran, Hong Thi and Naert, Thomas and Noelanders, Rivka and Hajamohideen, Amin and Beneteau, Claire and de Sousa, Sergio B. and Karaman, Birsen and Latypova, Xenia and Basaran, Seher and Yucel, Esra Borklu and Tan, Thong Teck and Vlaeminck, Lena and Nayak, Shalini S. and Shukla, Anju and Girisha, Katta Mohan and Le Caignec, Cedric and Soshnikova, Natalia and Uyguner, Zehra Oya and Vleminckx, Kris and Barker, Nick and Kayserili, Hulya and Reversade, Bruno},
  issn         = {0028-0836},
  journal      = {NATURE},
  language     = {eng},
  number       = {7706},
  pages        = {564--569},
  publisher    = {Nature Publishing Group},
  title        = {RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6},
  url          = {http://dx.doi.org/10.1038/s41586-018-0118-y},
  volume       = {557},
  year         = {2018},
}

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