title: WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals.
abstract: Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1.
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA Department II of Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors: Martin
authors: M
authors: Kann
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Eunnyung
authors: E
authors: Bae
authors: Department II of Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors: Maximilian O
authors: MO
authors: Lenz
authors: Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218, USA.
authors: Liangji
authors: L
authors: Li
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: BaoTran
authors: B
authors: Trannguyen
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Valerie A
authors: VA
authors: Schumacher
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Mary E
authors: ME
authors: Taglienti
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Liliana
authors: L
authors: Bordeianou
authors: Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada C1A 4P3.
authors: Sunny
authors: S
authors: Hartwig
authors: Department II of Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors: Markus M
authors: MM
authors: Rinschen
authors: Department II of Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne, University of Cologne, 50931 Cologne, Germany.
authors: Bernhard
authors: B
authors: Schermer
authors: Department II of Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne, University of Cologne, 50931 Cologne, Germany.
authors: Thomas
authors: T
authors: Benzing
authors: Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218, USA.
authors: Chen-Ming
authors: CM
authors: Fan
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA Harvard Stem Cell Institute, Cambridge, MA 02138, USA jordan.kreidberg@childrens.harvard.edu.
authors: Jordan A
authors: JA
authors: Kreidberg
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D018345:Mice, Knockout; D023421:Models, Animal; D009399:Nephrons / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D025721:WT1 Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D012333:RNA, Messenger; D025721:WT1 Proteins; D005346:Fibroblast Growth Factors; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; D051057:Proto-Oncogene Proteins c-akt
keywords: Fibroblast growth factor signaling; Kidney development; Mouse; Nephron progenitor cell