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Loss of Sprouty1 rescues renal agenesis caused by Ret mutation
Esteban J Rozen1, Hagen Schmidt, Xavier Dolcet
1Cell Signaling and Apoptosis Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain.
Abstract:
Renal morphogenesis requires a balance between positive and negative signals, which are provided in part by the receptor tyrosine kinase Ret and the putative tumor suppressor Sprouty1, respectively. Tyrosine 1062 of Ret is a binding site for several adaptor and effector proteins, such as Grb2/Sos/Ras, which activate the ERK pathway. Mice lacking Ret tyrosine 1062 nearly mimic the phenotype of Ret-knockout mice, which includes renal agenesis. Sprouty1 regulates Ret activity by modulating the ERK pathway, but the mechanism by which this occurs is uncertain. Here, we show that loss of Sprouty1 rescues the renal agenesis and early postnatal lethality caused by lack of Ret tyrosine 1062. The kidneys and lower urinary tracts of double-mutant mice developed normally. This effect was specific to the urinary system, because loss of Sprouty1 did not rescue the defects in the enteric nervous system characteristic of animals lacking Ret tyrosine 1062. These results suggest that Sprouty1 can modulate ERK signaling downstream of Ret, independent of Grb2/Sos/Ras, during renal morphogenesis.
Insights
Loss of Sprouty1 rescues renal agenesis in mice lacking Ret tyrosine 1062, restoring kidney development. This suggests Sprouty1 modulates Ret signaling independently of Grb2/Sos/Ras during kidney morphogenesis.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Renal morphogenesis relies on balanced signals from receptor tyrosine kinase Ret and tumor suppressor Sprouty1.
- Ret tyrosine 1062 is crucial for activating the ERK pathway via adaptor proteins like Grb2/Sos/Ras.
- Loss of Ret tyrosine 1062 leads to renal agenesis, mimicking Ret-knockout phenotypes.
Purpose of the Study:
- To investigate the role of Sprouty1 in modulating Ret signaling during renal development.
- To determine if Sprouty1 regulates Ret activity independently of the Grb2/Sos/Ras pathway.
- To elucidate the mechanism by which Sprouty1 influences ERK signaling downstream of Ret.
Main Methods:
- Generation and analysis of double-mutant mice lacking both Ret tyrosine 1062 and Sprouty1.
- Phenotypic assessment of renal and enteric nervous system development in mutant mice.
- Evaluation of ERK pathway modulation by Sprouty1 downstream of Ret.
Main Results:
- Loss of Sprouty1 rescued renal agenesis and early lethality in mice lacking Ret tyrosine 1062.
- Kidney and lower urinary tract development were normalized in double-mutant mice.
- Sprouty1's rescue effect was specific to the urinary system, not rescuing enteric nervous system defects.
Conclusions:
- Sprouty1 negatively regulates Ret signaling during renal morphogenesis.
- Sprouty1 modulates ERK signaling downstream of Ret, independent of Grb2/Sos/Ras.
- Targeting Sprouty1 may offer therapeutic potential for congenital kidney disorders.
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