RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6
| Autor: | Katta M. Girisha, Xenia Latypova, Zehra Oya Uyguner, Marc Leushacke, Seher Başaran, Esra Börklü Yücel, Emmanuelle Szenker-Ravi, Bruno Reversade, Sérgio B. Sousa, Muznah Khatoo, Umut Altunoglu, Kris Vleminckx, Birsen Karaman, Nick Barker, Célia Bosso-Lefèvre, Lena Vlaminck, Amin Hajamohideen, Claire Beneteau, Shalini S. Nayak, Cédric Le Caignec, Thong Teck Tan, Thomas Naert, Hong Thi Tran, Hülya Kayserili, Natalia Soshnikova, Anju Shukla, Rivka Noelanders |
|---|---|
| Přispěvatelé: | AR&D - Amsterdam Reproduction & Development, ACS - Diabetes & metabolism, Center for Reproductive Medicine, ACS - Heart failure & arrhythmias |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Apical ectodermal ridge Male Ubiquitin-Protein Ligases Xenopus Limb Deformities Congenital Receptors G-Protein-Coupled 03 medical and health sciences Gene Knockout Techniques Mice Limb development Animals Humans Receptor RSPO2 Oncogene Proteins Multidisciplinary biology HEK 293 cells LGR5 Wnt signaling pathway Extremities Fibroblasts biology.organism_classification Cell biology DNA-Binding Proteins 030104 developmental biology HEK293 Cells Phenotype Intercellular Signaling Peptides and Proteins Female |
| Zdroj: | Nature, 557(7706), 564-569. Nature Publishing Group |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. Independently of the LGR4/5/6 receptors, RSPO2 acts as a direct antagonistic ligand to RNF43 and ZNRF3 during embryogenesis, and specifies the position and number of limbs that an embryo should form. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink