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FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse.
K E Hentges1, B Sirry, A C Gingeras
1Gallo Center, University of California at San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA.
Summary
A mutation in the FKBP-12-rapamycin associated protein (FRAP) gene highlights its essential role in embryonic development. Early embryo exposure to rapamycin causes developmental issues similar to the FRAP mutation, indicating teratogenic effects.
Area of Science:
- Molecular Biology
- Developmental Biology
- Biochemistry
Background:
- FKBP-12-rapamycin associated protein (FRAP), also known as mTOR, is a serine/threonine kinase involved in cell growth and proliferation.
- FRAP signaling regulates mRNA translation via p70s6k and 4E-BP1, and its inhibition by rapamycin causes cell cycle arrest.
- Rapamycin is an immunosuppressant and an investigational anti-cancer agent, but its in vivo function, particularly in embryonic development, is not fully understood.
Purpose of the Study:
- To investigate the in vivo function of FRAP during mammalian embryonic development.
- To determine if rapamycin exhibits teratogenic activity by examining its effects on early embryonic development.
Main Methods:
- Identification and characterization of a loss-of-function mutation in the mouse FRAP gene.
- Treatment of early mouse embryos with rapamycin.
- Phenotypic analysis of FRAP mutant and rapamycin-treated embryos.
Main Results:
- A loss-of-function mutation in the mouse FRAP gene demonstrates FRAP's requirement for embryonic development.
- Rapamycin treatment of early embryos produced a phenotype identical to that of the FRAP mutant.
- These findings indicate that rapamycin possesses teratogenic properties.
Conclusions:
- FRAP kinase activity is essential for normal mammalian embryonic development.
- Rapamycin treatment during early embryogenesis results in developmental abnormalities, highlighting its teratogenic potential.