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Combined deficiencies of Src, Fyn, and Yes tyrosine kinases in mutant mice
P L Stein1, H Vogel, P Soriano
1Program in Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
Abstract:
Three members of the Src family of tyrosine kinases, src, fyn, and yes, are broadly expressed throughout mouse development. Mutations in the c-src and fyn genes were shown previously to lead to restricted nonoverlapping phenotypes only in a subset of cells in which these kinases are expressed. In this work we show that a mutation in the yes gene does not lead to an overt phenotype. Except for brain, the level or distribution of related kinases is not altered in major tissues. To gain further insight into the possibility that these kinases compensate for each other, animals deficient in multiple src-kinases were generated. Whereas most of the src/fyn or src/yes double mutants die perinatally, a substantial proportion of fyn/yes double mutants are viable but undergo degenerative renal changes leading to diffuse segmental glomerulosclerosis. Taken together, these data are consistent with the hypothesis that, at least in some cells, these kinases are able to compensate for the loss of the other related kinases.
Insights
Src, Fyn, and Yes kinases are crucial for mouse development. Compensatory roles were observed in double mutants, with Fyn/Yes deficiency causing kidney disease, supporting kinase functional redundancy.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Src family tyrosine kinases (Src, Fyn, Yes) are broadly expressed during mouse development.
- Individual mutations in c-src and fyn genes result in limited phenotypes.
- A mutation in the yes gene alone does not cause an observable phenotype.
Purpose of the Study:
- To investigate the functional redundancy and compensatory roles among Src, Fyn, and Yes kinases.
- To understand the consequences of combined deficiencies in these related kinases.
Main Methods:
- Generation of genetically modified mice deficient in multiple Src family kinases (Src, Fyn, Yes).
- Phenotypic analysis of single and double knockout mouse models.
- Assessment of kinase levels and distribution in major tissues.
Main Results:
- Most src/fyn and src/yes double mutants exhibit perinatal lethality.
- A significant portion of fyn/yes double mutants survive but develop kidney degeneration, specifically diffuse segmental glomerulosclerosis.
- No significant alterations in the levels or distribution of related kinases were observed in major tissues of single mutants, except in the brain.
Conclusions:
- Src, Fyn, and Yes kinases exhibit functional compensation, particularly evident in double mutant scenarios.
- The fyn/yes double mutant phenotype highlights the critical role of these kinases in maintaining renal homeostasis.
- These findings support the hypothesis that related kinases can compensate for each other's loss of function in specific cellular contexts.