Damping down translation in the germline

In many species, the reproductive cells of the germline can only form properly if certain mRNAs are prevented from translating into proteins before they have been transported to precise target locations in the egg and the appropriate developmental stage has been reached. In a study published in Developmental Cell, members of the Laboratory for Germline Development (Akira Nakamura, Team Leader) reported that, in the fruit fly Drosophila, this translational repression is achieved by a newly identified complex formed by three associating proteins.

RNA activity during Drosophila oogenesis involves a number of sequential processes. The Drosophila oocyte shares cytoplasm with neighboring nurse cells via an incomplete cell membrane, allowing mRNAs and proteins from the nurse cells to be transported to the oocyte in the form of ribonucleoproteins. Following their export from the nurse cell nuclei, mRNAs are translationally repressed, or ‘masked,’ and transported to specified regions of the oocyte, where they establish fixed and precise localizations and regain their ability to undergo translation. In one example of this critically important regulation, the translation of the RNA for the maternal gene oskar, which has critical functions in embryonic patterning and the formation of germline cells, is repressed during its transport to the posterior pole of the oocyte. This transcript-specific repression is known to be mediated by the protein Bruno, which binds to the 3' UTR of oskar mRNA, but the underlying mechanisms for this have remained obscure.

In the Developmental Cell study, the Nakamura lab demonstrated that an ovarian protein, Cup, is also required to inhibit the premature translation of oskar mRNA, and that Cup achieves this by binding to a second protein, eIF4E, a 5' cap-binding general translation initiation factor. Association with Cup prevents eIF4E from binding with a different partnering molecule, eIF4G, and thereby inhibits the initiation of translation.

Findings that a mutant form of Cup lacking the sequence with which it binds eIF4E failed to repress oskar translation in vivo, that Cup interacts with Bruno in a yeast two-hybrid assay, and that the Cup-eIF4E complex associates with Bruno in an immunoprecipitation assay, suggest that these three proteins form a complex that achieves translational repression by interactions with both the 3' and 5' ends of the oskar mRNA. A similar model of protein interactions is observed in the translational repression of the cyclin-B1 mRNA in the Xenopus African clawed frog, indicating that the paradigm of translational repression through the 5'/3' interactions is conserved across species.