In human females, meiosis I is completed prior to birth. The oocyte then arrests at meiosis II until puberty whereupon it undergoes maturation and ovulation and is ready to be fertilized. Upon fertilization, embryonic development ensues. At the end of meiosis I oocytes accumulate a stockpile of mRNAs that are (a) necessary for oocyte growth (?oogenic RNAs?), and (b) that are contributed maternally to the embryo (?maternal RNAs?). Once early embryonic development is complete however, degradation of the maternal RNAs is critical for reprogramming gene expression to transition to a totipotent embryo and enable embryonic genome activation. Errors in generation and/or protection of the oogenic and maternal RNAs grossly affect oogenesis; in contrast errors in the degradation of oogenic and maternal RNAs in the embryo affect embryonic development. Taken together, such errors are a major cause of human infertility and birth defects. Molecular mechanisms that regulate oogenic and maternal RNA generation and timely degradation are thus critical to understand, and remain to be fully elucidated. Using C. elegans meiosis I oocytes as our model system we identified that the nutritionally regulated RAS/ERK signaling pathway directly controls Dicer and Drosha, small RNA biogenesis enzymes, during meiosis I, to mediate normal oogenesis. Additionally, Dicer needs to be dephosphorylated to enable normal embryonic progression. We propose that progression of oogenesis is enabled through suppression of small RNAs, likely because oogenic RNAs are protected from degradation for translational regulation. Conversely, embryonic development likely ensues because of degradation of the maternal RNAs upon activation of the small RNAs. Together, these observations lead to the model 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, with direct implications to understanding both infertility and birth defects.
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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