Small RNA Pathways in Mammalian Gametogenesis

基础和临床研究表明，多种非编码rna和小rna在生殖细胞的发育和质量中发挥着重要而多样的作用，包括减数分裂过程中的X/Y沉默、基因调控、DNA损伤反应和保护基因组免受转座因子的侵害。事实上，已知哺乳动物生殖细胞含有多种小RNA，包括小干扰RNA （siRNA）、微RNA （miRNA）和种系特异性plwi相互作用RNA （piRNA）。然而，它们在配子体发生和人类不育中的机制作用在很大程度上尚未明确。康奈尔生殖基因组学中心（CRG）成立于2006年，已经在小RNA生物学领域发展了新兴的优势，以解决我们在理解上的这些空白。这些研究的目的是阐明小RNA途径在产生可存活的整倍体配子的事件中的作用。项目一（PI: Andrew Crimson）将定义精子发生过程中小RNA表达和小RNA靶点的时间谱，重点关注小鼠I前期的开始和进展；项目二（PI: Darius Paduch）将探索microRNAs在人类男性生殖细胞和体细胞室中的作用和表达，并将研究不育男性睾丸小rna谱的变化；项目III （PI: Paula Cohen）将探索Argonaute小RNA结合蛋白家族在小鼠减数分裂I前期沉默的关键过程中的作用；和Project IV （PI: John Schimenti）将研究哺乳动物生殖细胞中DNA复制许可的过程是如何通过microRNA介导的转录后控制来控制的。提出了三个核心：行政核心、外展核心和RNA测序核心，后者对所有SCCPIR成员开放。总的来说，这些研究代表了迄今为止哺乳动物配子发生中最全面的小RNA途径分析，并将提供小RNA调控过程的前沿项目，这将是SCCPIR网络中独特而及时的补充。对生殖系中小RNA途径的比较分析的综合关注可能极大地有助于理解这些途径如何发挥作用，以确保产生健康的配子。

DESCRIPTION (provided by applicant): Basic and clinical research is revealing that various noncoding and small RNAs play important and diverse roles in germ cell development and quality, including X/Y silencing during meiosis, gene regulation, DNA damage responses, and protection of the genome against transposable elements. Indeed, mammalian germ cells are known to harbor multiple small RNA species, including small interfering RNAs (siRNA), microRNAs (miRNA), and germline-specific PlWI-interacting RNAs (piRNA). However, their mechanistic roles in gametogenesis and human infertility are largely uncharacterized. The Cornell Center for Reproductive Genomics (CRG), established in 2006, has developed emerging strengths in the area of small RNA biology to address these gaps in our understanding. The goal of these studies is to elucidate the role of small RNA pathways in the events that give rise to viable euploid gametes. Four projects are proposed: Project I (PI: Andrew Crimson) will define the temporal profile of small RNA expression and small RNA targets throughout spermatogenesis, focusing on the onset of, and progression through, prophase I in the mouse; Project II (PI: Darius Paduch) will explore the roles and expression of microRNAs in human male germ cell and somatic compartments, and will examine changes in the profiles of testicular small RNAs In infertile men; Project III (PI: Paula Cohen) will explore he role of the Argonaute family of small RNA binding proteins in the critical process of meiotic silencing during prophase I in mice; and Project IV (PI: John Schimenti) will examine how the process of DNA replication licensing in mammalian germ cells is controlled by post-transcriptional control mediated by microRNA, miR34. Three cores are proposed: an Administrative core, and Outreach Core and an RNA sequencing core, the latter being open to all SCCPIR members. Collectively, these studies represent the most comprehensive analysis of small RNA pathways in mammalian gametogenesis to date, and will provide a cutting-edge program in small RNA regulatory processes that will be a unique and timely addition to the SCCPIR network. The combined focus on comparative analysis of small RNA pathways in the germline is likely to contribute greatly to the understanding of how these pathways may function to ensure the production of healthy gametes.