The regulation of the mammalian maternal-to-embryonic transition by eukaryotic translation initiation factor 4E
Eukaryotic translation initiation factor 4E (eIF4E) mediates CAP-dependent translation. Genetic and inhibitor studies show its expression was required for the successful transition from maternal to embryonic control of mouse embryo development. eIF4E was in the oocyte and in the cytoplasm soon after fertilization, and at each stage of early development. Functional knockout (Eif4e−/-) by PiggyBac (PB) [Act-RFP] transposition caused peri-implantation embryonic lethality due to the failure of normal epiblast formation. Maternal stores of eIF4E supported development up to the 2-4-cell stage after which new expression occurred from both alleles. Inhibition of the maternally acquired stores of eIF4E (4EGI-1 inhibitor) resulted in a block at the 2-cell stage. eIF4E activity was required for new protein synthesis in the 2-cell embryo and knockout embryos had lower translational activity than wildtype embryos. 4E-BP1 is a hypophosphorylation-dependent negative regulator of eIF4E. mTOR activity was required for 4E-BP1 phosphorylation and inhibiting mTOR retarded embryo development. This study shows that eIF4E activity is regulated at key embryonic transitions in the mammalian embryo and is essential for the successful transition to embryonic control of development.