Regulation of the mammalian maternal-to-embryonic transition by eukaryotic translation initiation factor 4E

Abstract

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.

Selective Translation of Maternal mRNA by eIF4E1B Controls Oocyte to Embryo Transition

“…[ 23 ] It has been reported that eIF4E is distributed evenly and also present in the vicinity of chromosomes after GVBD during oocyte maturation. [ 50 ] Through a comparison of the eIF4E1B targets with eIF4E targets, it was found a group of genes overlapped with the genes targeted to eIF4E1B. GO analysis revealed the overlapped function between eIF4E1B and eIF4E targeted genes including the process of the meiotic cell cycle (Figure 5F).…”

Embryonic arrest: causes and implications

“…Mutations in other MEGs have also been associated with human preimplantation embryo arrest, including CDC20 (cell division cycle 20), which helps the transition from metaphase to anaphase [63]; TRIP13 (thyroid hormone receptor interactor 13), which is a component of the spindle assembly checkpoint [64,65 ▪▪ ]; BTG4 (B-cell translocation gene 4), which mediates degradation of maternal mRNAs upon maternal-to-zygotic transition [66]. Studies in model systems support these findings and identify additional MEGs associated with embryonic developmental arrest [58,67–75] (Table 1).…”

“…A number of studies associated TUBB8 mutations with oocyte maturation defects ]; BTG4 (B-cell translocation gene 4), which mediates degradation of maternal mRNAs upon maternal-to-zygotic transition [66]. Studies in model systems support these findings and identify additional MEGs associated with embryonic developmental arrest [58,[67][68][69][70][71][72][73][74][75] (Table 1).…”

Spatial positioning of preimplantation mouse embryo cells is regulated by mTORC1 and m 7 G-cap-dependent translation at the 8- to 16-cell transition

“…encoding ANK2 [ 55 ]). Post-fertilization, mTOR directed phosphorylation of EIF4EBP1 is reported as an important translational regulator of the maternal-to-embryonic transition [ 56 ]. In early mouse blastocysts (but not earlier cleavage stages), partial pharmacological mTORi (targeting mTORC1 and mTORC2) results in prolonged but reversible and viable ex vivo paused development, akin to natural hormonally induced in vivo diapause [ 57 ].…”