RNF43 和 ZNRF3 的 RSPO2 抑制独立于 LGR4/5/6 控制肢体发育,Nature

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RNF43 和 ZNRF3 的 RSPO2 抑制独立于 LGR4/5/6 控制肢体发育
Nature ( IF 50.5 ) Pub Date : 2018-05-01 , DOI: 10.1038/s41586-018-0118-y
Emmanuelle Szenker-Ravi ₁ , Umut Altunoglu ₂ , Marc Leushacke ₁ , Célia Bosso-Lefèvre _{1,

3} , Muznah Khatoo ₁ , Hong Thi Tran ₄ , Thomas Naert ₄ , Rivka Noelanders ₄ , Amin Hajamohideen ₁ , Claire Beneteau ₅ , Sergio B de Sousa _{6,

7} , Birsen Karaman ₂ , Xenia Latypova ₅ , Seher Başaran ₂ , Esra Börklü Yücel ₈ , Thong Teck Tan ₁ , Lena Vlaminck _{4,

9} , Shalini S Nayak ₁₀ , Anju Shukla ₁₀ , Katta Mohan Girisha ₁₀ , Cédric Le Caignec _{5,

11} , Natalia Soshnikova ₁₂ , Zehra Oya Uyguner ₂ , Kris Vleminckx _{4,

13} , Nick Barker _{1,

14,

15} , Hülya Kayserili _{2,

8} , Bruno Reversade _{1,

3,

8,

16,

17}

Affiliation

Institute of Medical Biology, A*STAR, Singapore, Singapore.
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
Department of Paediatrics, National University of Singapore, Singapore, Singapore.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
CHU Nantes, Service de Génétique Médicale, Nantes, France.
Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
University Clinic of Genetics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium.
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
INSERM, UMR1238, Bone Sarcoma and Remodeling of Calcified Tissue, Université Bretagne Loire, Nantes, France.
Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany.
Center for Medical Genetics, Ghent University, Ghent, Belgium.
Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK.
Institute of Molecular and Cellular Biology, A*STAR, Singapore, Singapore.
Reproductive Biology Laboratory, Academic Medical Center (AMC), Amsterdam-Zuidoost, The Netherlands.

四种 R-spondin 分泌配体 (RSPO1–RSPO4) 通过其同源 LGR4、LGR5 和 LGR6 受体发挥作用，以放大 WNT 信号传导 1–3。在这里，我们报告了人类中导致四肢不全综合征的一系列隐性 RSPO2 突变，其特征是肺发育不全和四肢完全缺失。功能研究显示与 LGR4/5/6 受体以及 RNF43 和 ZNRF3 跨膜连接酶的结合受损，WNT 增强降低，这与等位基因的严重程度相关。然而，出乎意料的是，小鼠中 Lgr4、Lgr5 和 Lgr6 的三重和普遍敲除并未重现已知的 Rspo2 或 Rspo3 功能丧失表型。此外，在三重敲除 Lgr4/5/6 细胞中内源性消耗或添加外源性 RSPO2 或 RSPO3 仍会影响 WNT 反应性。反而，我们发现非洲爪蟾胚胎中 rnf43 和 znrf3 的同时缺失足以触发多余肢体的生长。我们的结果表明，没有 LGR4/5/6 受体的 RSPO2 作为 RNF43 和 ZNRF3 的直接拮抗配体，它们共同构成了控制肢体规范的主开关。这些发现对再生医学和 WNT 相关癌症具有直接意义。独立于 LGR4/5/6 受体，RSPO2 在胚胎发生过程中充当 RNF43 和 ZNRF3 的直接拮抗配体，并指定胚胎应该的肢体位置和数量形式。它们共同构成了控制肢体规范的主开关。这些发现对再生医学和 WNT 相关癌症具有直接意义。独立于 LGR4/5/6 受体，RSPO2 在胚胎发生过程中充当 RNF43 和 ZNRF3 的直接拮抗配体，并指定胚胎应该的肢体位置和数量形式。它们共同构成了控制肢体规范的主开关。这些发现对再生医学和 WNT 相关癌症具有直接意义。独立于 LGR4/5/6 受体，RSPO2 在胚胎发生过程中充当 RNF43 和 ZNRF3 的直接拮抗配体，并指定胚胎应该的肢体位置和数量形式。

"点击查看英文标题和摘要"

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

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.

更新日期：2018-05-01

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