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.
All data generated or analysed during this study are included in the manuscript and supporting files.Source data files have been provided for Figures 2B, 2C, 2F, 3C, 3D, 4E, 5D, 5F 6C, Suppl. Figure 1A
- Andreas Schedl
- Andreas Schedl
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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)).
- Roel Nusse, Stanford University, United States
© 2020, Vidal et al.
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