Functions of MOV10L1 in piRNA biogenesis and germ cell development

MOV10L1 在 piRNA 生物发生和生殖细胞发育中的功能

基本信息

批准号：
8607581
负责人：
Peijing Jeremy Wang
金额：
$ 29.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607581
关键词：
Address Binding Biochemical Genetics Biogenesis Biological Biological Process Bombyx Bombyx mori Cell Line Cell Nucleus Cells Chromatin Congenital Abnormality Coupled Cultured Cells DNA DNA Transposable Elements DNA strand break Deletion Mutation Development Diagnosis Etiology Exhibits Fertility Fertilization Functional RNA Gene Silencing Genetic Models Genome Genomics Germ Cells Germ Lines Homologous Gene Left Male Infertility Male Sterility Maps Meiosis MicroRNAs Mus Mutant Strains Mice Organism Other Genetics Ovarian Ovary Pachytene Stage Pathway interactions Pattern Physiological Play Point Mutation Pregnancy loss Prevention Protamines Protein Binding Proteins RNA RNA Helicase RNA Interference Repression Retrotransposon Role Seminal Silk Small Interfering RNA Small RNA Sorting - Cell Movement Spermatids Spermiogenesis Staging Sterility Superhelical DNA System Testis Variant Zebrafish Zygonema base chromatin remodeling deep sequencing feeding fly human disease innovation insight male member mouse genome mouse model mutant novel piRNA postnatal transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of the current application is to elucidate the biogenesis and function of a novel class of small non-coding RNAs, the piRNAs. RNA interference has emerged as a major regulatory mechanism in gene silencing in which small non-coding RNAs function as sequence-specific guides. MicroRNAs, a relatively well- characterized class of small non-coding RNAs, are essential for normal development and are implicated in many human diseases. In contrast, the biogenesis and function of piRNAs (Piwi-interacting RNAs), a diverse class of germline-specific small non-coding RNAs, is poorly understood. Recent studies in diverse organisms including fly, zebra fish, and mice have shown that Piwi proteins and piRNAs are required for silencing of transposable elements in the germline. We have found that MOV10L1, a putative RNA helicase, binds to all Piwi proteins and is an essential component of the piRNA pathway. Therefore, MOV10L1 is the only known master regulator of the mammalian piRNA pathway. Disruption of Mov10l1 leads to a loss of piRNAs and meiotic arrest in males. Using our unique Mov10l1 conditional mutant and other genetic models, we plan to: 1) investigate the chromatin integrity and functional competency of MOV10L1/piRNA-deficient round spermatids, 2) elucidate the role of MOV10L1 in the biogenesis and function of pachytene piRNAs, and 3) biochemically characterize the role of the MOV10L1 homologue in piRNA biogenesis in cultured silkworm (Bombyx mori) BmN4 ovarian cell lines. These studies will elucidate the mechanistic basis of piRNA biogenesis and a novel function for MOV10L1 and pachytene piRNAs in maintaining genome integrity during spermiogenesis. These studies will provide insight into etiology, diagnosis, and prevention of human diseases including male infertility and birth defects.

描述（由申请人提供）：本申请的长期目标是阐明一类新型小非编码RNA（piRNA）的生物发生和功能。 RNA 干扰已成为基因沉默的主要调节机制，其中小非编码 RNA 充当序列特异性向导。 MicroRNA 是一类相对明确的小非编码 RNA，对于正常发育至关重要，并且与许多人类疾病有关。相比之下，piRNA（Piwi 相互作用 RNA）（一种不同类型的种系特异性小非编码 RNA）的生物发生和功能知之甚少。最近对包括苍蝇、斑马鱼和小鼠在内的多种生物体的研究表明，Piwi 蛋白和 piRNA 是种系中转座元件沉默所必需的。我们发现 MOV10L1（一种假定的 RNA 解旋酶）可与所有 Piwi 蛋白结合，并且是 piRNA 途径的重要组成部分。因此，MOV10L1 是哺乳动物 piRNA 通路中唯一已知的主调节因子。 Mov10l1 的破坏会导致 piRNA 丢失和雄性减数分裂停滞。使用我们独特的Mov10l1条件突变体和其他遗传模型，我们计划：1）研究MOV10L1/piRNA缺陷的圆形精子细胞的染色质完整性和功能能力，2）阐明MOV10L1在粗线期piRNA的生物发生和功能中的作用，以及3) 生化表征 MOV10L1 同源物在培养物中 piRNA 生物发生中的作用蚕（Bombyx mori）BmN4 卵巢细胞系。这些研究将阐明 piRNA 生物发生的机制基础，以及 MOV10L1 和粗线期 piRNA 在精子发生过程中维持基因组完整性的新功能。这些研究将为包括男性不育症和出生缺陷在内的人类疾病的病因学、诊断和预防提供深入的见解。