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

Development. 2015 Aug 1;142(15):2564-73. doi: 10.1242/dev.122648. Epub 2015 Jun 26.

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.

Keywords: Dachsous 1; Fat4; Hippo pathway; Progenitor renewal; Stroma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Analysis of Variance
  • Animals
  • Cadherins / metabolism*
  • Cell Cycle Proteins
  • Cell Differentiation / physiology*
  • Cell Lineage / physiology
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Immunoblotting
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Nephrons / ultrastructure*
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction / physiology*
  • Stem Cells / cytology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • Cell Cycle Proteins
  • Dchs1 protein, mouse
  • Fat4 protein, mouse
  • Phosphoproteins
  • Yap protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases