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 Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. De Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan GirishaCédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, Bruno Reversade

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)564-569
Number of pages6
JournalNature
Volume557
Issue number7706
DOIs
Publication statusPublished - 24-05-2018

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Extremities
Ligands
Regenerative Medicine
Ligases
Xenopus
Embryonic Structures
Alleles
Phenotype
Lung
Mutation
Neoplasms
Tetra-amelia autosomal recessive

All Science Journal Classification (ASJC) codes

  • General

Cite this

Szenker-Ravi, E., Altunoglu, U., Leushacke, M., Bosso-Lefèvre, C., Khatoo, M., Thi Tran, H., ... Reversade, B. (2018). RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature, 557(7706), 564-569. https://doi.org/10.1038/s41586-018-0118-y
Szenker-Ravi, Emmanuelle ; Altunoglu, Umut ; Leushacke, Marc ; Bosso-Lefèvre, Célia ; Khatoo, Muznah ; Thi Tran, Hong ; Naert, Thomas ; Noelanders, Rivka ; Hajamohideen, Amin ; Beneteau, Claire ; De Sousa, Sergio B. ; Karaman, Birsen ; Latypova, Xenia ; Başaran, Seher ; Yücel, Esra Börklü ; Tan, Thong Teck ; Vlaminck, Lena ; Nayak, Shalini S. ; Shukla, Anju ; Girisha, Katta Mohan ; Le Caignec, Cédric ; Soshnikova, Natalia ; Uyguner, Zehra Oya ; Vleminckx, Kris ; Barker, Nick ; Kayserili, Hülya ; Reversade, Bruno. / RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. In: Nature. 2018 ; Vol. 557, No. 7706. pp. 564-569.
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Szenker-Ravi, E, Altunoglu, U, Leushacke, M, Bosso-Lefèvre, C, Khatoo, M, Thi Tran, H, Naert, T, Noelanders, R, Hajamohideen, A, Beneteau, C, De Sousa, SB, Karaman, B, Latypova, X, Başaran, S, Yücel, EB, Tan, TT, Vlaminck, L, Nayak, SS, Shukla, A, Girisha, KM, Le Caignec, C, Soshnikova, N, Uyguner, ZO, Vleminckx, K, Barker, N, Kayserili, H & Reversade, B 2018, 'RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6', Nature, vol. 557, no. 7706, pp. 564-569. https://doi.org/10.1038/s41586-018-0118-y

RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. / Szenker-Ravi, Emmanuelle; Altunoglu, Umut; Leushacke, Marc; Bosso-Lefèvre, Célia; Khatoo, Muznah; Thi Tran, Hong; Naert, Thomas; Noelanders, Rivka; Hajamohideen, Amin; Beneteau, Claire; De Sousa, Sergio B.; Karaman, Birsen; Latypova, Xenia; Başaran, Seher; Yücel, Esra Börklü; Tan, Thong Teck; Vlaminck, Lena; Nayak, Shalini S.; Shukla, Anju; Girisha, Katta Mohan; Le Caignec, Cédric; Soshnikova, Natalia; Uyguner, Zehra Oya; Vleminckx, Kris; Barker, Nick; Kayserili, Hülya; Reversade, Bruno.

In: Nature, Vol. 557, No. 7706, 24.05.2018, p. 564-569.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6

AU - Szenker-Ravi, Emmanuelle

AU - Altunoglu, Umut

AU - Leushacke, Marc

AU - Bosso-Lefèvre, Célia

AU - Khatoo, Muznah

AU - Thi Tran, Hong

AU - Naert, Thomas

AU - Noelanders, Rivka

AU - Hajamohideen, Amin

AU - Beneteau, Claire

AU - De Sousa, Sergio B.

AU - Karaman, Birsen

AU - Latypova, Xenia

AU - Başaran, Seher

AU - Yücel, Esra Börklü

AU - Tan, Thong Teck

AU - Vlaminck, Lena

AU - Nayak, Shalini S.

AU - Shukla, Anju

AU - Girisha, Katta Mohan

AU - Le Caignec, Cédric

AU - Soshnikova, Natalia

AU - Uyguner, Zehra Oya

AU - Vleminckx, Kris

AU - Barker, Nick

AU - Kayserili, Hülya

AU - Reversade, Bruno

PY - 2018/5/24

Y1 - 2018/5/24

N2 - 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.

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Szenker-Ravi E, Altunoglu U, Leushacke M, Bosso-Lefèvre C, Khatoo M, Thi Tran H et al. RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature. 2018 May 24;557(7706):564-569. https://doi.org/10.1038/s41586-018-0118-y