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      Stromal Fat4 acts non-autonomously with Dchs1/2 to restrict the nephron progenitor pool.

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          Abstract

          Regulation of the balance between progenitor self-renewal and differentiation is crucial to development. In the mammalian kidney, reciprocal signalling between three lineages (stromal, mesenchymal and ureteric) ensures correct nephron progenitor self-renewal and differentiation. Loss of either the atypical cadherin FAT4 or its ligand Dachsous 1 (DCHS1) results in expansion of the mesenchymal nephron progenitor pool, called the condensing mesenchyme (CM). This has been proposed to be due to misregulation of the Hippo kinase pathway transcriptional co-activator YAP. Here, we use tissue-specific deletions to prove that FAT4 acts non-autonomously in the renal stroma to control nephron progenitors. We show that loss of Yap from the CM in Fat4-null mice does not reduce the expanded CM, indicating that FAT4 regulates the CM independently of YAP. Analysis of Six2(-/-);Fat4(-/-) double mutants demonstrates that excess progenitors in Fat4 mutants are dependent on Six2, a crucial regulator of nephron progenitor self-renewal. Electron microscopy reveals that cell organisation is disrupted in Fat4 mutants. Gene expression analysis demonstrates that the expression of Notch and FGF pathway components are altered in Fat4 mutants. Finally, we show that Dchs1, and its paralogue Dchs2, function in a partially redundant fashion to regulate the number of nephron progenitors. Our data support a model in which FAT4 in the stroma binds to DCHS1/2 in the mouse CM to restrict progenitor self-renewal.

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          Author and article information

          Journal
          Development
          Development (Cambridge, England)
          1477-9129
          0950-1991
          Aug 1 2015
          : 142
          : 15
          Affiliations
          [1 ] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
          [2 ] Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
          [3 ] Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
          [4 ] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
          [5 ] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
          [6 ] Institut du Développement de Marseille, CNRS UMR 7288, France.
          [7 ] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 mcneill@lunenfeld.ca.
          Article
          dev.122648
          10.1242/dev.122648
          26116661
          ba689637-c164-4d73-8fff-169d29f87ea9
          © 2015. Published by The Company of Biologists Ltd.
          History

          Dachsous 1,Fat4,Hippo pathway,Progenitor renewal,Stroma
          Dachsous 1, Fat4, Hippo pathway, Progenitor renewal, Stroma

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