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FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling

Hongtao Zhang1, Mazdak Bagherie-Lachidan2, Caroline Badouel3

  • 1Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.

Developmental Cell
|March 12, 2019
PubMed

Insights

FAT4 mutations cause kidney disease by disrupting normal kidney development. This study reveals FAT4 interacts with RET to regulate its signaling, offering a new mechanism for kidney development control.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in FAT4 are linked to human kidney diseases, but the precise mechanisms are unclear.
  • Kidney development relies on precise signaling pathways, including the RET receptor tyrosine kinase.

Purpose of the Study:

  • To investigate the molecular mechanism by which FAT4 influences kidney development.
  • To elucidate the interaction between FAT4 and RET signaling in the developing kidney.

Main Methods:

  • Analysis of kidney development in Fat4 knockout mouse models.
  • Investigating the interaction between FAT4 and RET signaling components.
  • Conditional knockout studies to determine FAT4's role in regulating RET signaling.

Main Results:

  • Loss of Fat4 in mice leads to abnormal ureteric budding and excessive RET signaling.
  • Reducing levels of the RET ligand GDNF partially rescues Fat4 knockout kidney phenotypes.
  • FAT4 directly interacts with RET via its extracellular cadherin repeats, modulating RET-GFRA1-GDNF complex assembly and reducing RET signaling.

Conclusions:

  • FAT4 acts as a regulator of RET signaling during kidney development.
  • This interaction establishes a juxtacrine mechanism mediated by FAT4 controlling RET activity and kidney morphogenesis.
  • Understanding this FAT4-RET axis provides insights into kidney developmental disorders.
Keywords:
CAKUTFAT4RETVan Maldergem syndromecadherinkidney developmentnon-autonomous

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