1. Developmental Biology
  2. Stem Cells and Regenerative Medicine
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R-spondin signalling is essential for the maintenance and differentiation of mouse nephron progenitors

Research Article
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Cite this article as: eLife 2020;9:e53895 doi: 10.7554/eLife.53895

Abstract

During kidney development, WNT/b-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of nephron progenitor cells. Here we show in mice that the signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/b-catenin signalling and their genetic deletion leads to a rapid decline of nephron progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss of Bmp7 expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activate Lef1, Fgf8 and Wnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of R-spondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and reveal Lgr-dependent and independent functions for these ligands during kidney formation.

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Author details

  1. Valerie PI Vidal

    Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
    For correspondence
    valerie.vidal@unice.fr
    Competing interests
    The authors declare that no competing interests exist.
  2. Fariba Jian Motamedi

    Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Samah Rekima

    Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Elodie P Gregoire

    Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Emmanuelle Szenker-Ravi

    Institute of Medical Biology, A*STAR, Sinagapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Marc Leushacke

    Institute of Medical Biology, A*STAR, Sinagapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Bruno Reversade

    Institute of Medical Biology, A*STAR, Sinagapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4070-7997
  8. Marie-Christine Chaboissier

    Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0934-8217
  9. Andreas Schedl

    Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
    For correspondence
    schedl@unice.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9380-7396

Funding

European Commission (305608)

  • Andreas Schedl

Ligue Contre le Cancer (Equipe labelisee)

  • Andreas Schedl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The experiments described in this paper were carried out in compliance with the French and international animal welfare laws, guidelines and policies and were approved by the local ethics committee (PEA No NCE-2014-207 and PEA No: 2018060516474844 (V2)).

Reviewing Editor

  1. Roel Nusse, Stanford University, United States

Publication history

  1. Received: November 23, 2019
  2. Accepted: April 23, 2020
  3. Accepted Manuscript published: April 23, 2020 (version 1)
  4. Accepted Manuscript updated: May 1, 2020 (version 2)
  5. Version of Record published: May 15, 2020 (version 3)

Copyright

© 2020, Vidal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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