WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals
Autor: | Jordan A. Kreidberg, Thomas Benzing, Valérie Schumacher, Mary E. Taglienti, Maximilian Lenz, Chen-Ming Fan, Eunnyung Bae, Martin Kann, Markus M. Rinschen, Sunny Hartwig, Bernhard Schermer, Liliana Bordeianou, Liangji Li, BaoTran Trannguyen |
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Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
medicine.medical_specialty
Kidney development Cell Cycle Proteins Fibroblast growth factor urologic and male genital diseases GPI-Linked Proteins Receptor tyrosine kinase Organ Culture Techniques Internal medicine medicine Animals RNA Messenger Progenitor cell Promoter Regions Genetic WT1 Proteins Molecular Biology Protein kinase B Transcription factor Cell Proliferation Mice Knockout biology Cell growth urogenital system Stem Cells Proto-Oncogene Proteins c-ret Gene Expression Regulation Developmental DNA Nephrons Stem Cells and Regeneration Cell biology Enzyme Activation Fibroblast Growth Factors Endocrinology Gene Knockdown Techniques Models Animal biology.protein Signal transduction Proto-Oncogene Proteins c-akt Developmental Biology Protein Binding Signal Transduction |
Popis: | 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. |
Databáze: | OpenAIRE |
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