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bioRxiv · 10.1101/859959

Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

Vidal, V. P. I.·Gregoire, E.·Szenker, E.·Leushacke, M.·Reversade, B.·Chaboissier, M.-C.·Schedl, A.
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Abstract

During kidney development, WNT/{beta}-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of renal stem cells. Here we show that the two signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/{beta}-catenin signalling and their genetic deletion leads to a rapid decline of renal 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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Vidal, V. P. I., Gregoire, E., Szenker, E., Leushacke, M., Reversade, B., Chaboissier, M.-C., Schedl, A.. 2019-11-29. Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells. https://doi.org/10.1101/859959

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