Friday AJ , Keiper BD .

Figure 1. Models of mRNA translational repression and translation initiation complexes. (a) mRNAs are translationally repressed by RBPs that bind sequence recognition motifs in the 3′UTR. Protein-protein interactions with 4EBP-eIF4E-mRNA form stable mRNP complexes that inhibit the recruitment of eIF4E-bound mRNA to eIF4G, eIF4A (an mRNA helicase), and the ribosome. (b) Model of cap-dependent translation initiation utilizing the cap-binding protein eIF4E. Cap-bound mRNAs are recruited to the 40S ribosomal subunit by association with eIF4G and PABP. Association with eIF2 and eIF3 completes the 48S preinitiation complex. (c) Model of cap-independent translation. The “short” isoform of eIF4G lacking an eIF4E-binding domain is still capable of recruiting mRNA to the 40S ribosomal subunit with eIFs by binding directly to the 5′UTR.

Figure 2. Dynamic models for selective protein synthesis in germ cells. (a) A complex mixed population of mRNAs present in germ cells of various stages is selectively recruited for translation initiation by individual eIF4 isoforms. This positive selection occurs temporally as developing cells require new protein synthesis. Corresponding mRNA becomes derepressed, and the eIF4E-mRNA complex is recruited to the cap-dependent translation initiation complex by the “long” isoform of eIF4G. Other mRNAs are recruited by cap-independent translation initiation via the short eIF4G isoform that lacks the eIF4E binding domain. Episodes of selective mRNA translation by individual eIF4 isoforms drive critical germ cell fate decisions. (b) As new protein synthesis is required for germ cell renewal, growth, and differentiation, one pathway, or circuit, is activated for the translation of a certain population of stored mRNAs. mRNP complexes reach the first “translation on/off” switch at a point where bound RBPs (including eIF4 factors) undergo remodeling that results in mRNA derepression. Derepressed mRNAs following the cap-dependent circuit use a switch involving of one of the eIF4E isoforms. Successfully activating this switch, eIF4E-bound mRNA is recruited to the initiation complex via the long eIF4G. Alternatively derepressed mRNAs following the cap-independent circuit are made available for initiation recruitment via the short eIF4G in an analogous fashion. Both cap-dependent and cap-independent recruited mRNAs then reach a node in which eIF4A and ribosomes must be bound. (Note that in C. elegans and Drosophila germ cell mRNPs, eIF4A, or a homologous helicase, has been found to be prebound.) The 40S ribosomal subunit brings with it initiator Met-tRNA bound to eIF2. This step constitutes a “rheostat” in the circuit where the volume of protein synthesis can be limited by phosphorylation of eIF2. mRNAs completing this circuit are efficiently decoded into new proteins necessary for discrete germ cell developmental events.

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