XB-ART-54903Nature January 1, 2018; 557 (7706): 564-569.
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.
PubMed ID: 29769720
Article link: Nature
Species referenced: Xenopus
Genes referenced: lgr4 lgr5 rnf43 rspo1 rspo2 rspo3 znrf3
GO keywords: Wnt signaling pathway
Disease Ontology terms: bone development disease
OMIMs: TETRAAMELIA SYNDROME 1; TETAMS1
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References [+] :
Aoki, R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development. 2008, Pubmed