权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of stem cell differentiation during Drosophila oogenesis

果蝇卵子发生过程中干细胞分化的调控

基本信息

批准号：
10471420
负责人：
Prashanth Rangan
金额：
$ 33.72万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471420
关键词：
Binding Proteins Biological Models Cell Compartmentation Cell Maintenance ChIP-seq Chromatin Complex Congenital Abnormality Data Defect Deposition Disease Distributional Activity Dosage Compensation (Genetics)Drosophila genus Drosophila melanogaster Etiology Female Fertility Disorders Foxes Gametogenesis Genes Genetic Transcription Genomics Germ Cells Germ Lines Goals Histones Human Intrinsic factor Knowledge Lead Licensing Lysine Maintenance Mammals Mediating Meiosis Messenger RNA Methods Mitosis Mitotic Modeling Mutation Nature Oocytes Oogenesis Outcome Phase Phase Transition Phenocopy Production Proteins RNA-Binding Proteins Regulation Reporter Ribosomal Proteins Role Testing Translating Translations Work X Chromosome cofactor gain of function germline stem cells histone acetyltransferase improved in vivo insight loss of function male morphogens mutant next generation paralogous gene pluripotency polysome profiling programs recruit self renewing cell self-renewal stem cell differentiation stem cells transcriptome sequencing translation factor

项目摘要

Abstract The production of gametes is pivotal to launching the next generation. To generate gametes, germline stem cells (GSCs) must exit the mitotic program, which governs self-renewal and transit amplification, and initiate the meiotic program. While several germ cell intrinsic mechanisms that repress the meiotic program during the mitotic phase have been described, little is known about how the mitotic program is regulated. We have identified a specialized transcriptional complex that permits the expression of a germline-specific ribosomal protein that regulates the mitotic program and the shift to meiosis. We discovered an unexpected role for the conserved Male-specific lethal 3 (Msl3) protein in regulating female germline mitotic phase transcription. In Drosophila, Msl3 is part of the Dosage Compensation Complex (DCC) that upregulates transcription from the X chromosome in males. We find that msl3 is expressed in the mitotic phase of the female germ line, where it acts independently of the DCC to both promote GSC maintenance and transition into meiotic fate. Our data suggest that Msl3 recruits the histone acetyltransferase (HAT) activity of the Ada2a-Containing (ATAC) complex. We found that loss of msl3 and ATAC complex components lead to reduced transcription of a ribosomal protein, RpS19b. We find that RpS19b is expressed specifically in the germline mitotic stages and propose that it controls translation of factors such as RNA binding protein Fox 1 (Rbfox1) to regulate the mitosis- to-meiosis switch. The objective of this proposal is to uncover how Msl3 regulates the transition from the mitotic- to-meiotic program via RpS19b. Our central hypothesis is that Msl3 recruits HAT activity via the ATAC complex to promote transcription of RpS19b, which in turn regulates Rbfox1 translation. We plan to test our hypothesis with the following three specific aims: 1) Determine how Msl3 promotes oogenesis. 2) Determine the role of HATs in Msl3-dependent transcription. 3) Uncover the role and mechanism of RpS19b in oogenesis. The rationale for the proposed work is that insight into Msl3-mediated regulation of the mitotic-to-meiotic transition will illuminate how functional oocytes are generated. In mammals, Msl3 is part of the Male Specific Lethal (MSL) complex, which regulates maintenance and differentiation from the pluripotency program, suggesting a potential conserved function of Msl3 in stem cell compartments.

摘要配子的产生是下一代出生的关键。为了产生配子，生殖干细胞（GSC）必须退出有丝分裂程序，该程序控制自我更新和转运扩增，并启动细胞增殖。减数分裂程序虽然在减数分裂过程中抑制减数分裂程序的几种生殖细胞内在机制，尽管有丝分裂期的研究已经被描述过，但关于有丝分裂程序是如何被调节的却知之甚少。我们有确定了一个专门的转录复合物，允许表达生殖系特异性调节有丝分裂程序和向减数分裂转变的核糖体蛋白。我们发现了一个保守的雄性特异性致死3（Msl 3）蛋白在调节雌性生殖系有丝分裂中的意外作用阶段转录在果蝇中，Ms 13是剂量补偿复合物（DCC）的一部分，男性的X染色体转录。我们发现msl 3在雌性的有丝分裂期表达，生殖系，其中它独立于DCC起作用以促进GSC维持和向减数分裂的过渡命运我们的数据表明，Ms 13募集Ada 2a-含有Ada 2a的细胞的组蛋白乙酰转移酶（HAT）活性。（ATAC）复合物。我们发现msl 3和ATAC复合物成分的缺失导致了一个转录因子的转录减少。核糖体蛋白RpS 19 b。我们发现RpS 19 b在生殖细胞有丝分裂期特异性表达，提出它控制RNA结合蛋白Fox 1（Rbfox 1）等因子的翻译，以调节有丝分裂- 减数分裂开关该提案的目的是揭示Msl 3如何调节从有丝分裂-增殖的过渡。通过RpS 19 b进行减数分裂程序。我们的中心假设是Msl 3通过ATAC复合物募集HAT活性促进RpS 19 b的转录，RpS 19 b反过来又调节Rbfox 1的翻译。我们计划验证我们的假设具有以下三个具体目的：1）确定Ms 13如何促进卵子发生。2)确定的作用 Msl 3依赖性转录中的HAT。3)揭示RpS 19 b在卵子发生中的作用和机制。的所提出的工作的基本原理是对Msl 3介导的有丝分裂到减数分裂转变的调节的深入了解将阐明功能性卵母细胞是如何产生的在哺乳动物中，Ms 13是雄性特异性致死（MSL）的一部分。复合物，调节多能性程序的维持和分化，这表明一种潜在的 Ms 13在干细胞区室中的保守功能。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A switch in the mode of Wnt signaling orchestrates the formation of germline stem cell differentiation niche in Drosophila.

Wnt 信号传导模式的转换协调了果蝇生殖系干细胞分化生态位的形成。

DOI：
10.1371/journal.pgen.1007154
发表时间：
2018
期刊：
PLoS genetics
影响因子：
4.5
作者：
Upadhyay,Maitreyi;Kuna,Michael;Tudor,Sara;MartinoCortez,Yesenia;Rangan,Prashanth
通讯作者：
Rangan,Prashanth

Transposon Dysregulation Modulates dWnt4 Signaling to Control Germline Stem Cell Differentiation in Drosophila.

DOI：
10.1371/journal.pgen.1005918
发表时间：
2016-03
期刊：
PLoS genetics
影响因子：
4.5
作者：
Upadhyay M;Martino Cortez Y;Wong-Deyrup S;Tavares L;Schowalter S;Flora P;Hill C;Nasrallah MA;Chittur S;Rangan P
通讯作者：
Rangan P

Tip60 complex promotes expression of a differentiation factor to regulate germline differentiation in female Drosophila.