Musashi regulates the temporal order of mRNA translation during Xenopus oocyte maturation

Abstract

A strict temporal order of maternal mRNA translation is essential for meiotic cell cycle progression in oocytes of the frog Xenopus laevis. The molecular mechanisms controlling the ordered pattern of mRNA translational activation have not been elucidated. We report a novel role for the neural stem cell regulatory protein, Musashi, in controlling the translational activation of the mRNA encoding the Mos proto-oncogene during meiotic cell cycle progression. We demonstrate that Musashi interacts specifically with the polyadenylation response element in the 3' untranslated region of the Mos mRNA and that this interaction is necessary for early Mos mRNA translational activation. A dominant inhibitory form of Musashi blocks maternal mRNA cytoplasmic polyadenylation and meiotic cell cycle progression. Our data suggest that Musashi is a target of the initiating progesterone signaling pathway and reveal that late cytoplasmic polyadenylation element-directed mRNA translation requires early, Musashi-dependent mRNA translation. These findings indicate that Musashi function is necessary to establish the temporal order of maternal mRNA translation during Xenopus meiotic cell cycle progression.

Ringo/Cyclin-dependent Kinase and Mitogen-activated Protein Kinase Signaling Pathways Regulate the Activity of the Cell Fate Determinant Musashi to Promote Cell Cycle Re-entry in Xenopus Oocytes

“…However, Mos, the primary MAP kinase activator in oocytes (27)(28)(29), is itself regulated through translational activation by Musashi, suggesting that Musashi must be initially activated by a MAP kinase-independent mechanism (5). Consistent with this hypothesis, it has been previously shown that treatment of oocytes with the MAP kinase signaling inhibitor UO126 does not prevent initial polyadenylation or translation of the Mos mRNA (5,30).…”

“…Translation of Ringo then induces Ringo/CDK activity, leading to the initial activation of Musashi and Musashi-dependent mRNA translation, as reported in this study. Musashi-dependent mRNA translation then mediates subsequent CPEB activation and translation of late class, CPEdependent mRNAs (5,13). The coordinated action of these mRNA translational regulators serves to promote and maintain MPF activity and cell cycle progression.…”

“…We have previously demonstrated that activation of Musashi function is required to mediate early class mRNA translation before GVBD and completion of meiosis I (5). Musashi-dependent translation of the early class Mos mRNA results in MAP kinase activation and subsequent CPEB-mediated, late class mRNA translation (5,13). The sequential function of Musashi-and CPEB-dependent translational control promotes and maintains M-phase promoting factor activity (MPF, cyclin B/CDK) and cell cycle progression up to metaphase of meiosis II (9).…”

“…Oocyte cell cycle re-entry occurs in the absence of active gene transcription, and the proteins required for this process are synthesized from preexisting mRNAs in a specific temporal pattern that is predominantly directed through regulatory sequences within the mRNA 3Ј-untranslated regions (3,4). In the oocytes of the frog Xenopus laevis, multiple mRNA-binding proteins have been implicated in sequence-specific mRNA translational control, including the developmental regulator Pumilio, the stem cell self-renewal factor Musashi, and the cytoplasmic polyadenylation element-binding protein (CPEB) 5 (5)(6)(7)(8). However, the mechanism by which the function of these mRNA translational control proteins is coordinated to produce a temporally integrated pattern of protein expression is not fully understood (9,10).…”

Translational regulation of the cell cycle: when, where, how and why?

“…Pum2 exerts its effects at least in part by affecting the interaction between the RNA-binding protein DAZL (deleted in azoospermia-like) and the embryonic PABP, but it also may affect polyadenylation [31]. Another translational regulator, Musashi, is implicated in promoting the translation of Mos and Cyclin B5 by binding to the MBE (Musashi-binding element) and acting together with CPE to influence polyadenylation [94,99,100].…”