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

Area of Science:

• Developmental Biology
• Cell Biology
• Molecular Biology

Background:

• Kidney development relies on balanced progenitor self-renewal and differentiation, controlled by reciprocal signaling between stromal, mesenchymal, and ureteric lineages.
• Loss of FAT4 or Dachsous 1 (DCHS1) leads to expansion of the mesenchymal nephron progenitor pool (condensing mesenchyme, CM), potentially via YAP misregulation.

Purpose of the Study:

• To elucidate the non-autonomous role of FAT4 in regulating nephron progenitor populations within the developing mammalian kidney.
• To determine if FAT4's regulation of the CM is dependent on the Hippo pathway component YAP.
• To investigate the genetic interactions between FAT4, Six2, and Dchs1/2 in controlling nephron progenitor homeostasis.

Main Methods:

• Tissue-specific gene deletions in mice to analyze FAT4 function in distinct renal lineages.
• Genetic analysis of double mutants (e.g., Six2(-/-);Fat4(-/-)) to assess genetic dependencies.
• Electron microscopy to examine cellular organization.
• Gene expression analysis to identify altered signaling pathways.

Main Results:

• FAT4 acts non-autonomously in the renal stroma to control nephron progenitors, independent of YAP in the CM.
• Excess progenitors in Fat4 mutants are dependent on Six2, a key regulator of progenitor self-renewal.
• FAT4 mutations disrupt cellular organization and alter expression of Notch and FGF pathway components.
• Dchs1 and its paralogue Dchs2 exhibit partial redundancy in regulating nephron progenitor numbers.

Conclusions:

• FAT4 in the renal stroma restricts nephron progenitor self-renewal by interacting with DCHS1/2 in the CM.
• This mechanism operates independently of YAP and highlights the importance of stromal-mesenchymal interactions in kidney development.
• Dchs1 and Dchs2 play partially redundant roles in maintaining progenitor pool size.