ERK mediated control of Dicer and Drosha in C. elegans

项目总结 在人类女性中，减数分裂I在出生前完成。然后卵母细胞在减数分裂II期停止，直到青春期。 然后它经历成熟和排卵，并准备受精。受精后，胚胎 发展随之而来。在减数分裂结束时，卵母细胞积累了大量(A)必需的mRNAs。 对于卵母细胞的生长(“卵源核糖核酸”)，以及(B)母体对胚胎的贡献(“母体核糖核酸”)。 然而，一旦早期胚胎发育完成，母体RNA的降解对 重新编程基因表达，以过渡到全能胚胎，并使胚胎基因组激活。 卵源和母体RNA的产生和/或保护的错误严重影响卵子的发生；相反 胚胎中卵源和母体RNA降解的错误会影响胚胎发育。已被占用 总而言之，这些错误是人类不孕不育和出生缺陷的主要原因。分子机制 因此，调节卵源和母体RNA的产生和及时降解是理解和 仍有待充分阐明。以线虫减数分裂I期卵母细胞为模型系统，我们鉴定了 营养调控的RAS/ERK信号通路直接控制小RNA的生物发生 在减数分裂I期间，调节正常卵子发生的酶。此外，迪格尔需要去磷酸化以 使胚胎能够正常发育。我们认为卵子发生的进展是通过 抑制小RNA，可能是因为卵源RNA受到保护，不会因翻译 监管。相反，胚胎发育可能是由于母体rna的退化而发生的。 在激活小RNA时。总而言之，这些观察结果导致了信号诱导的模型 DICER和DROSHA的调节协调卵子发生过程中母体RNA的产生和保护 它们在胚胎中的及时降解，对理解不孕不育和出生有直接意义 缺陷。

PROJECT SUMMARY 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.