In human females, oocytes complete meiosis I at birth, and enter a long period of meiotic II arrest until onset of meiotic maturation at puberty. At the end of meiosis I oocytes are packed with maternal RNAs, which, upon fertilization of the mature oocyte, are necessary for early embryonic development. The RNAs are degraded later in embryogenesis to enable embryonic genome activation. Errors during the generation and/or protection of the maternal RNAs may adversely affect oogenesis and result in infertility. Similarly, errors in degrading the maternal RNAs during embryogenesis can cause birth defects. Thus, mechanisms that coordinate the generation and protection of maternal RNA during oogenesis with their timely degradation in the embryo are critical for understanding the molecular basis of infertility and birth defects; such mechanisms remain unknown. Using C. elegans meiosis I oocytes as our model system we identified that the nutritionally regulated RAS/ERK signaling pathway phosphorylates Dicer and Drosha, small RNA biogenesis enzymes (Inset Figure). Specifically, we found that ERK-mediated phosphorylation of Dicer and Drosha, inhibited the production of endo-siRNAs (and likely miRNAs), potentially to protect the maternal mRNAs. Conversely, dephosphorylation of Dicer (and likely Drosha) prior to fertilization resumed the production of small RNAs, potentially to degrade the maternal mRNAs and enable embryonic genome activation. Strikingly, we find that phosphorylated Dicer localized in the nucleus, and may be involved with transcriptional elongation of maternal mRNAs. We also identified a new miRNA-like species that are generated upon loss of Dicer activity. We named them Dicer-Depletion-Dependent miRNAs (D3-miRNAs) their function remains unknown. Collectively, our findings support the hypothesis that signal- induced regulation of Dicer and Drosha coordinates the generation and protection of maternal RNAs during oogenesis with their timely degradation in the embryo.
R01GM098200 ORIGINAL NARRATIVE The proposal seeks to investigate the role of RAS/ERK signaling-induced regulation of Dicer and Drosha, and how that coordinates the generation and protection of maternal RNAs with their timely degradation in the embryo. Because meiosis I is a fundamental and conserved process across metazoans, the knowledge gained from this research has implications to understanding both infertility and birth defects. Also, RAS/ERK pathway is oncogenic and Dicer and Drosha are tumor suppressors, the study has strong relevance to mechanisms of cancer development.
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