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

Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx (), Nick Barker (), Hülya Kayserili () and Bruno Reversade ()
Additional contact information
Emmanuelle Szenker-Ravi: Institute of Medical Biology, A*STAR
Umut Altunoglu: Istanbul Medical Faculty, Istanbul University
Marc Leushacke: Institute of Medical Biology, A*STAR
Célia Bosso-Lefèvre: Institute of Medical Biology, A*STAR
Muznah Khatoo: Institute of Medical Biology, A*STAR
Hong Tran: Ghent University
Thomas Naert: Ghent University
Rivka Noelanders: Ghent University
Amin Hajamohideen: Institute of Medical Biology, A*STAR
Claire Beneteau: Service de Génétique Médicale
Sergio B. Sousa: Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra
Birsen Karaman: Istanbul Medical Faculty, Istanbul University
Xenia Latypova: Service de Génétique Médicale
Seher Başaran: Istanbul Medical Faculty, Istanbul University
Esra Börklü Yücel: Koç University School of Medicine (KUSOM)
Thong Teck Tan: Institute of Medical Biology, A*STAR
Lena Vlaminck: Ghent University
Shalini S. Nayak: Manipal University
Anju Shukla: Manipal University
Katta Mohan Girisha: Manipal University
Cédric Caignec: Service de Génétique Médicale
Natalia Soshnikova: Institute of Molecular Biology (IMB) gGmbH
Zehra Oya Uyguner: Istanbul Medical Faculty, Istanbul University
Kris Vleminckx: Ghent University
Nick Barker: Institute of Medical Biology, A*STAR
Hülya Kayserili: Istanbul Medical Faculty, Istanbul University
Bruno Reversade: Institute of Medical Biology, A*STAR

Nature, 2018, vol. 557, issue 7706, 564-569

Abstract: Abstract The four R-spondin secreted ligands (RSPO1–RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1–3. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0118-y

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