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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
Summary
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.
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