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Regulation of Spermatogenesis by X-linked miRNAs

X 连锁 miRNA 对精子发生的调节

基本信息

批准号：
8644815
负责人：
John R MCCARREY
金额：
$ 38.4万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644815
关键词：
Accounting Active Sites Cell Nucleus Cell physiology Cells Characteristics Collaborations Contraceptive Agents Cytoplasm DNA Data Defect Development Diagnosis Employee Strikes Euchromatin Female Fertility Functional RNA Gene Cluster Gene Silencing Genes Germ Germ Cells Grant In Vitro Knock-out Lead Link Male Infertility Mediating Meiosis Messenger RNA MicroRNAs Molecular Molecular Genetics Molecular Profiling Mus National Institute of Child Health and Human Development Nuclear Organ Pattern Phase Physical condensation Play Post-Transcriptional Regulation Process Production Prophase Proteins Regulation Reporting Role Sex Chromosomes Somatic Cell Spermatocytes Spermatogenesis Spermiogenesis Staging Structural Genes Technology Testing Testis Translating X Chromosome X Inactivation Y Chromosome blastomere structure chromatin modification deep sequencing design gene repression homologous recombination in vivo insight knockout gene mRNA Stability male mammalian genome mutant novel public health relevance sex sperm cell

项目摘要

DESCRIPTION (provided by applicant): Meiotic sex chromosome inactivation (MSCI) during spermatogenesis is characterized by transcriptional silencing of genes on both the X and Y chromosomes in mid to late pachytene spermatocytes. MSCI is believed to result from meiotic silencing of unpaired DNA because the X and Y chromosomes remain largely unpaired throughout first meiotic prophase. Thus, unlike X-chromosome inactivation in female embryonic or somatic cells, where 25-30% of X-linked structural genes have been reported to escape inactivation, there have been no previous reports of genes that escape the silencing effects of MSCI in primary spermatocytes. However, we recently discovered that many X-linked microRNAs (miRNAs) are transcribed and processed in pachytene spermatocytes. This unprecedented escape from MSCI suggests that these miRNAs participate in one or more critical functions at this stage of spermatogenesis. This is corroborated by our preliminary finding that chimeric mice carrying a high percentage of cells bearing a knockout of a major cluster of X-linked miRNA genes display a fertility defect manifest as a block during the meiotic phase of spermatogenesis. This is significant because despite recent reports describing expression of an abundance of miRNAs and other small, non-coding RNAs during spermatogenesis, essentially nothing is known about the function of any of these. In this application, we first propose to investigate the molecular mechanism by which these X-linked miRNA genes escape MSCI (Aim 1). We then propose to test two hypotheses (which are not mutually exclusive) regarding function of these miRNAs, including their role as post- transcriptional regulators of autosomal mRNAs that are synthesized during meiosis but not translated until the postmeiotic period (Aim 2), and their role in regulating the process of MSCI itself (Aim 3). This study is highly novel in that it is designed to reveal an unprecedented mechanism of escape from MSCI, and to identify actual functions of those X-linked miRNAs that undergo this escape during spermatogenesis.

描述（由申请方提供）：精子发生期间减数分裂性染色体失活（MSCI）的特征是粗线期中期至晚期精母细胞中X和Y染色体上的基因转录沉默。MSCI被认为是由未配对DNA的减数分裂沉默引起的，因为X和Y染色体在整个第一次减数分裂前期大部分保持未配对。因此，与女性胚胎或体细胞中的X染色体失活不同，其中25-30%的X连锁结构基因已被报道逃脱失活，先前没有报道初级精母细胞中逃脱MSCI沉默效应的基因。然而，我们最近发现，许多X-连锁microRNA（miRNA）的转录和加工粗线期精母细胞。这种前所未有的从MSCI中逃逸的现象表明，这些miRNAs在精子发生的这个阶段参与了一种或多种关键功能。我们的初步发现证实了这一点，即携带高百分比的X连锁miRNA基因主要簇敲除细胞的嵌合小鼠在精子发生的减数分裂阶段显示出生育缺陷，表现为阻滞。这是重要的，因为尽管最近的报道描述了大量的miRNA和其他小的非编码RNA在精子发生过程中的表达，但基本上对这些中的任何一个的功能都一无所知。在本申请中，我们首先提出研究这些X连锁的miRNA基因逃避MSCI（Aim 1）的分子机制。然后，我们提出测试关于这些miRNA的功能的两个假设（它们不是相互排斥的），包括它们作为在减数分裂期间合成但直到减数分裂后期才翻译的常染色体mRNA的转录后调节剂的作用（Aim 2），以及它们在调节MSCI本身的过程中的作用（Aim 3）。这项研究是非常新颖的，因为它旨在揭示一种前所未有的从MSCI逃逸的机制，并确定在精子发生过程中经历这种逃逸的X-连锁miRNA的实际功能。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mark it for destruction: a novel role of mRNA methylation in maternal-to-zygotic transition†.

将其标记为破坏：mRNA 甲基化在母体向合子转变中的新作用。

DOI：
10.1093/biolre/iox016
发表时间：
2017
期刊：
Biology of reproduction
影响因子：
3.6
作者：
Yan,Wei
通讯作者：
Yan,Wei

Rsx is a metatherian RNA with Xist-like properties in X-chromosome inactivation.

DOI：
10.1038/nature11171
发表时间：
2012-07-12
期刊：
NATURE
影响因子：
64.8
作者：
Grant, Jennifer;Mahadevaiah, Shantha K.;Khil, Pavel;Sangrithi, Mahesh N.;Royo, Helene;Duckworth, Janine;McCarrey, John R.;VandeBerg, John L.;Renfree, Marilyn B.;Taylor, Willie;Elgar, Greg;Camerini-Otero, R. Daniel;Gilchrist, Mike J.;Turner, James M. A.
通讯作者：
Turner, James M. A.

piRNA-independent PIWI function in spermatogenesis and male fertility.

不依赖于 piRNA 的 PIWI 在精子发生和男性生育能力中发挥作用。