Loss of Sprouty1 rescues renal agenesis caused by Ret mutation.
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.
Rozen
Esteban J
EJ
Cell Signaling and Apoptosis Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain.
Schmidt
Hagen
H
Dolcet
Xavier
X
Basson
M Albert
MA
Jain
Sanjay
S
Encinas
Mario
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006579:Heterozygote; D007633:Keratins / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D014551:Urinary Tract / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D007633:Keratins; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases