ERK mediated control of Dicer and Drosha in C. elegans

ERK 介导的线虫 Dicer 和 Drosha 控制

• 批准号: 9380220
• 负责人: Swathi Arur
• 金额: $ 32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380220
• 关键词: Affect; Biogenesis; Biological Models; Birth; Caenorhabditis elegans; Cancer Biology; Catalytic Domain; Cell Nucleus; ChIP-seq; Chromatin; Computer Simulation; Congenital Abnormality; Development; Embryo; Embryonic Development; Enzymes; Fertilization; Fluorescent in Situ Hybridization; Gene Expression; Generations; Genetic Models; Genetic Transcription; Genome; Germ Lines; Growth; Histones; Human; Infertility; Knowledge; Lead; Malignant Neoplasms; Maternal Messenger RNA; Mediating; Meiosis; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular; Mus; Names; Nuclear; Nucleotides; Nutritional; Oncogenic; Oocytes; Oogenesis; Ovulation; Pathway interactions; Pattern; Phenotype; Phosphorylation; Process; Production; Protein Dephosphorylation; Puberty; RNA; RNA Polymerase II; Regulation; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Small RNA; Sterility; Testing; Time; Totipotent; Transcript; Transcription Elongation; Transcriptional Activation; Translational Regulation; Tumor Suppressor Proteins; Validation; Zebrafish; base; embryonic stem cell; human female; in vivo; tissue culture; transcriptome sequencing

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.

项目摘要 在人类女性中，减数分裂I在出生前完成。然后卵母细胞停止在减数分裂II，直到青春期 在那里它经历成熟和排卵并准备受精。受精后，胚胎 发展环境在减数分裂I结束时，卵母细胞积累了大量的mRNA，这些mRNA是（a）必需的 用于卵母细胞生长的RNA（“卵原RNA”），和（B）母体贡献给胚胎的RNA（“母体RNA”）。 然而，一旦早期胚胎发育完成，母体RNA的降解对于发育至关重要。 重编程基因表达以过渡到全能胚胎并使胚胎基因组激活成为可能。 卵子发生和母体RNA的产生和/或保护错误严重影响卵子发生;相反， 胚胎中卵子和母体RNA降解的错误影响胚胎发育。采取 这些错误加在一起是人类不育和出生缺陷的主要原因。分子机制 调节卵子和母体RNA的产生和及时降解因此是理解的关键， 还有待于充分阐明。利用C.作为我们的模型系统，我们发现， 营养调节的RAS/ERK信号通路直接控制Dicer和Drosha，小RNA生物合成 酶，在减数分裂I，介导正常卵子发生。此外，Dicer需要去磷酸化， 使胚胎正常发育。我们认为卵子发生的进程是通过 抑制小RNA，可能是因为卵源RNA被保护免于降解， 调控相反，胚胎发育可能由于母体RNA的降解而增强， 在小RNA的激活后。总之，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 随着它们在胚胎中的及时降解，直接影响到对不孕症和生育的理解， 缺陷