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Published on: November 10, 2021
Role of fibroblast growth factor receptor signaling in kidney development
1Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA. batescm@upmc.edu
Abstract:
Fibroblast growth factor receptors (Fgfrs) are expressed throughout the developing kidney. Several early studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB). Transgenic mice that over-express a dominant negative receptor isoform develop renal aplasia/severe dysplasia, confirming the importance of Fgfrs in renal development. Furthermore, global deletion of Fgf7, Fgf10, and Fgfr2IIIb (isoform that binds Fgf7 and Fgf10) in mice leads to small kidneys with fewer collecting ducts and nephrons. Deletion of Fgfrl1, a receptor lacking intracellular signaling domains, causes severe renal dysgenesis. Conditional targeting of Fgf8 from the MM interrupts nephron formation. Deletion of Fgfr2 from the UB results in severe ureteric branching and stromal mesenchymal defects, although loss of Frs2α (major signaling adapter for Fgfrs) in the UB causes only mild renal hypoplasia. Deletion of both Fgfr1 and Fgfr2 in the MM results in renal aplasia with defects in MM formation and initial UB elongation and branching. Loss of Fgfr2 in the MM leads to many renal and urinary tract anomalies as well as vesicoureteral reflux. Thus, Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.
Insights
Fibroblast growth factor receptors (Fgfrs) are crucial for kidney development. Their signaling pathways regulate the formation and patterning of virtually all renal lineages throughout kidney development.
Area of Science:
- Developmental Biology
- Renal Physiology
- Molecular Biology
Background:
- Fibroblast growth factor receptors (Fgfrs) are present in the developing kidney.
- Exogenous fibroblast growth factors (Fgfs) influence metanephric mesenchyme (MM) and ureteric bud (UB) growth and maturation.
- Previous studies highlight the significance of Fgfr signaling in renal development.
Purpose of the Study:
- To investigate the critical role of Fgfr signaling in kidney development.
- To elucidate the specific contributions of Fgfrs and Fgfs to renal lineage patterning.
Main Methods:
- Analysis of transgenic mice over-expressing dominant-negative Fgfr isoforms.
- Gene deletion studies (global and conditional) targeting Fgf7, Fgf10, Fgfr2IIIb, Fgfrl1, Fgf8, Fgfr2, and Frs2α.
- Examination of renal development, including renal aplasia, dysplasia, hypoplasia, and ureteric branching defects.
Main Results:
- Over-expression of dominant-negative Fgfrs leads to renal aplasia/severe dysplasia.
- Deletion of Fgf7, Fgf10, and Fgfr2IIIb results in smaller kidneys with reduced collecting ducts and nephrons.
- Loss of Fgfrl1 causes severe renal dysgenesis; Fgf8 deletion from MM interrupts nephron formation.
- Fgfr2 deletion in UB causes severe ureteric branching defects; Frs2α loss in UB leads to mild hypoplasia.
- Combined Fgfr1/Fgfr2 deletion in MM results in renal aplasia and impaired MM/UB development.
- Fgfr2 loss in MM causes renal and urinary tract anomalies, including vesicoureteral reflux.
Conclusions:
- Fgfr signaling is essential for the patterning of all renal lineages during kidney development.
- Disruptions in Fgfr signaling lead to a spectrum of renal developmental abnormalities.
- Fgfrs play critical roles at both early and late stages of kidney formation.
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