Regulation of proliferation and differentiation in the male germ line adult stem cell lineage

雄性生殖系成体干细胞谱系增殖和分化的调节

基本信息

  • 批准号:
    10160936
  • 负责人:
  • 金额:
    $ 85.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary / Abstract The switch from proliferation to differentiation is a key regulatory point in the adult stem cell lineages that underlie tissue maintenance and repair, and failure to cleanly switch may contribute to genesis of cancer. My laboratory has long used the Drosophila male germ line as a model to investigate how self-renewal, proliferation and differentiation are regulated in adult stem cell lineages. Several lines of our inquiry have recently converged on the molecular mechanisms underlying the developmentally programmed transition from mitotic proliferation to onset of meiosis and differentiation, implicating a number of molecular and cellular mechanisms in regulating this critical switch. We find that RNA binding proteins involved in translational control and alternative splicing act cell autonomously to regulate the cessation of proliferation and that progression of differentiation requires communication from associated somatic support cells. We discovered that a developmentally regulated alternate choice of site at which certain nascent transcripts are cut to form 3' ends, leading to production of novel mRNA isoforms with shortened 3'UTRs, controls dramatic changes in the suite of proteins expressed in differentiating spermatocytes compared to proliferating spermatogonia. We found that dramatic changes in chromatin open over 2000 new promoters with novel core sequence structure to turn on the new cell type specific transcription program when cells initiate spermatocyte differentiation. Some of the earliest genes turned on in this differentiation program encode chromatin associated proteins that prevent spurious opening of normally cryptic promoters, thus preventing massive misexpression of genes associated with the wrong cell type. Other transcripts upregulated with differentiation onset encode cell type-specific translational regulators that delay production of core G2/M cell cycle machinery to program the extended G2 phase of meiotic prophase. Over the next 5 years, we propose to map how these processes collaborate to form the regulatory circuitry that initiates then executes the switch from proliferation to differentiation. We will investigate how the RNA binding proteins Bam and Bgcn trigger the switch from mitosis to meiosis by repressing expression of the alternative splice factor HOW, identify candidate substrates of HOW by immunoprecipitation followed by RNA-Seq, and assess their function in vivo, including whether they communicate with adjacent somatic support cells. We will investigate how the switch in proteins expressed due to alternative 3' end cut site selection on nascent transcripts is regulated and influences differentiation. We will investigate how the differentiation program is kept off in precursor cells and how cell-type specific chromatin regulators and proteins that recruit them to target loci set up the new transcription program for differentiation. To elucidate how the developmental program remodels the cell cycle, we will investigate how cell-type specific RNA binding proteins first repress, then activate translation of cyclin B during meiotic prophase and how the DAZ homolog Boule regulates progression into the meiotic divisions. .
项目摘要/摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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MARGARET T FULLER其他文献

MARGARET T FULLER的其他文献

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{{ truncateString('MARGARET T FULLER', 18)}}的其他基金

Genetics and Developmental Biology Training Program
遗传学和发育生物学培训计划
  • 批准号:
    10630969
  • 财政年份:
    2022
  • 资助金额:
    $ 85.15万
  • 项目类别:
Genetics and Developmental Biology Training Program
遗传学和发育生物学培训计划
  • 批准号:
    10410329
  • 财政年份:
    2022
  • 资助金额:
    $ 85.15万
  • 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
  • 批准号:
    10417163
  • 财政年份:
    2020
  • 资助金额:
    $ 85.15万
  • 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
  • 批准号:
    10630243
  • 财政年份:
    2020
  • 资助金额:
    $ 85.15万
  • 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
  • 批准号:
    10449061
  • 财政年份:
    2020
  • 资助金额:
    $ 85.15万
  • 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
  • 批准号:
    10675340
  • 财政年份:
    2020
  • 资助金额:
    $ 85.15万
  • 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
  • 批准号:
    10200518
  • 财政年份:
    2020
  • 资助金额:
    $ 85.15万
  • 项目类别:
Alternative polydenylation and the regulation of male germ cell differentiation
选择性多聚腺苷酸化和雄性生殖细胞分化的调节
  • 批准号:
    8822709
  • 财政年份:
    2014
  • 资助金额:
    $ 85.15万
  • 项目类别:
Alternative polydenylation and the regulation of male germ cell differentiation
选择性多聚腺苷酸化和雄性生殖细胞分化的调节
  • 批准号:
    8936332
  • 财政年份:
    2014
  • 资助金额:
    $ 85.15万
  • 项目类别:
PROJECT 2: TRANSLATIONAL REGULATION OF THE MEIOTIC CELL CYCLE IN THE MALE.
项目 2:男性减数分裂细胞周期的翻译调控。
  • 批准号:
    8638813
  • 财政年份:
    2014
  • 资助金额:
    $ 85.15万
  • 项目类别:

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