title: WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors.
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.
authors.affiliation: 1] Institute of Biology Valrose, Université de Nice-Sophia, F-06108 Nice, France [2] Inserm, UMR1091, F-06108 Nice, France [3] CNRS, UMR7277, F-06108 Nice, France [4].
authors.forename: Fariba Jian
authors.initials: FJ
authors.lastname: Motamedi
authors.affiliation: 1] Institute of Biology Valrose, Université de Nice-Sophia, F-06108 Nice, France [2] Inserm, UMR1091, F-06108 Nice, France [3] CNRS, UMR7277, F-06108 Nice, France [4].
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Badro
authors.affiliation: 1] Institute of Biology Valrose, Université de Nice-Sophia, F-06108 Nice, France [2] Inserm, UMR1091, F-06108 Nice, France [3] CNRS, UMR7277, F-06108 Nice, France [4].
authors.forename: Michael
authors.initials: M
authors.lastname: Clarkson
authors.affiliation: 1] Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland [2] Functional Genomics Center Zurich, UZH/ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: M Rita
authors.initials: MR
authors.lastname: Lecca
authors.affiliation: 1] Institute of Biology Valrose, Université de Nice-Sophia, F-06108 Nice, France [2] Inserm, UMR1091, F-06108 Nice, France [3] CNRS, UMR7277, F-06108 Nice, France [4] Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [5] CSIRO Animal, Food & Health Sciences, Preventative Health Flagship, North Ryde, New South Wales 2113, Australia.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Bradford
authors.affiliation: 1] Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Fabian A
authors.initials: FA
authors.lastname: Buske
authors.affiliation: MDC for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.affiliation: MDC for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: 1] Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland [2] Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: André W
authors.initials: AW
authors.lastname: Brändli
authors.affiliation: 1] Institute of Biology Valrose, Université de Nice-Sophia, F-06108 Nice, France [2] Inserm, UMR1091, F-06108 Nice, France [3] CNRS, UMR7277, F-06108 Nice, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019295:Computational Biology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008817:Mice, Mutant Strains; D009924:Organ Culture Techniques; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D025721:WT1 Proteins
chemical_list: D019485:Bone Morphogenetic Proteins; D012097:Repressor Proteins; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; D005346:Fibroblast Growth Factors