WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors

Fariba Jian Motamedi, Danielle A. Badro, Michael Clarkson, M Rita Lecca, Stephen T. Bradford, Fabian A. Buske, Kathrin Saar, Norbert Hübner, André W. Brändli and Andreas Schedl ()
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Fariba Jian Motamedi: Institute of Biology Valrose, Université de Nice-Sophia
Danielle A. Badro: Institute of Biology Valrose, Université de Nice-Sophia
Michael Clarkson: Institute of Biology Valrose, Université de Nice-Sophia
M Rita Lecca: Institute of Pharmaceutical Sciences, ETH Zurich
Stephen T. Bradford: Institute of Biology Valrose, Université de Nice-Sophia
Fabian A. Buske: Garvan Institute of Medical Research
Kathrin Saar: MDC for Molecular Medicine
Norbert Hübner: MDC for Molecular Medicine
André W. Brändli: Institute of Pharmaceutical Sciences, ETH Zurich
Andreas Schedl: Institute of Biology Valrose, Université de Nice-Sophia

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Kidney organogenesis requires the tight control of proliferation, differentiation and apoptosis of renal progenitor cells. How the balance between these cellular decisions is achieved remains elusive. The Wilms’ tumour suppressor Wt1 is required for progenitor survival, but the molecular cause for renal agenesis in mutants is poorly understood. Here we demonstrate that lack of Wt1 abolishes fibroblast growth factor (FGF) and induces BMP/pSMAD signalling within the metanephric mesenchyme. Addition of recombinant FGFs or inhibition of pSMAD signalling rescues progenitor cell apoptosis induced by the loss of Wt1. We further show that recombinant BMP4, but not BMP7, induces an apoptotic response within the early kidney that can be suppressed by simultaneous addition of FGFs. These data reveal a hitherto unknown sensitivity of early renal progenitors to pSMAD signalling, establishes FGF and pSMAD signalling as antagonistic forces in early kidney development and places WT1 as a key regulator of pro-survival FGF signalling pathway genes.

Date: 2014
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DOI: 10.1038/ncomms5444

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