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.
journal_name
Naturejournal_title
Natureauthors
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,Girisdoi
10.1038/s41586-018-0118-ysubject
Has Abstractpub_date
2018-05-01 00:00:00pages
564-569issue
7706eissn
0028-0836issn
1476-4687pii
10.1038/s41586-018-0118-yjournal_volume
557pub_type
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