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

Nature
Emmanuelle Szenker-RaviBruno Reversade

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 ca...Continue Reading

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Datasets Mentioned

BETA
SRP136052

Methods Mentioned

BETA
exome sequencing
co-immunoprecipitation
genotyping
IEC
exome
biopsy
PCR
Transfection
protein assay
Assay

Software Mentioned

OGT
ANNOVAR
Burrows Aligner BWA
GATK
Agilent Oligonucleotide Array - Based CGH for
Picard
Samtools
BATCH
Illumina Karyostudio & Bluefuse Multi Softwares
PRISM5

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