FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse

The FKBP-12-rapamycin associated protein (FRAP, also known as mTOR and RAFT -1) is a member of the phosphoinositide kinase related kinase family. FRAP has serine/threonine kinase activity and mediates the cellular response to mitogens through signaling to p70s6 kinase (p70(s6k)) and 4E-BP1, resulting in an increase in translation of subsets of cellular mRNAs. Translational up-regulation is blocked by inactivation of FRAP signaling by rapamycin, re sulting in G, cell cycle arrest. Rapamycin is used as an immunosuppressant for kidney transplants and is currently under investigation as an antiproli ferative agent in tumors because of its ability to block FRAP activity. Alt hough the role of FRAP has been extensively studied in vitro, characterizat ion of mammalian FRAP function in vivo has been limited to the immune syste m and tumor models. Here we report the identification of a loss-of-function mutation in the mouse FRAP gene, which illustrates a requirement for FRAP activity in embryonic development. Our studies also determined that rapamyc in treatment of the early embryo results in a phenotype indistinguishable f rom the FRAP mutant, demonstrating that rapamycin has teratogenic activity.