Stem Cell Renewal and Differentiation in Spermatogenesis

精子发生中的干细胞更新和分化

• 批准号: 8825507
• 负责人: STEPHEN Francis DINARDO
• 金额: $ 34.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825507
• 关键词: Address; Adopted; Affect; Architecture; Behavior; Biology; Cell Communication; Cells; ChIP-seq; Chromatin; Cues; Cyst; Data; Development; Disease; Drosophila genus; Ectopic Expression; Epithelial; Epithelial cyst; Epithelium; Event; Family; Funding; Gene Targeting; Genes; Germ Cells; Gonadal structure; Health; Homeodomain Proteins; Human; Image; Immigration; Lateral; Life; Location; Maps; Membrane; Mesenchymal; Modeling; Nature; Open Reading Frames; Pathway interactions; Population; Positioning Attribute; Production; Property; Proteins; Regenerative Medicine; Role; Running; Signal Pathway; Signal Transduction; Somatic Cell; Specific qualifier value; Spermatogenesis; Stem cells; System; Testing; Testis; Time; Tissues; Work; Zinc Fingers; cell behavior; cell motility; daughter cell; epithelial to mesenchymal transition; gain of function; germline stem cells; interest; migration; mutant; self-renewal; stem; stem cell division; stem cell fate; stem cell niche; trafficking

DESCRIPTION (provided by applicant): There is intense interest in the circuits that guide stem cell behavior. While niches are essential to the behavior of many tissue-specific stem cells, it is not understood how the niche is specified and assembled in a tissue, and then how it executes control over the stem cell pool. Understanding these interactions will be crucial to use these cells in regenerative medicine. This proposal addresses how are niches specified, organized and function, and utilizes one of the most well-understood stem cell-niche systems, the Drosophila testis. Here, a small group of cells (hub cells) act as part of the niche, leading t the activation of signaling pathways in adjacent cells. In this way, nearby somatic cells take on cyst stem cell fate (CySC), while nearby germline cells, intermingled with these CySCs, take on germline stem cell fate (GSC). Hub formation, and the attendant attachment of stem cells, is the major architectural event of gonadogenesis. The specification and placement of hub cells among somatic gonadal precursors (SGPs) generates an anteriorly-anchored proliferation center that will drive spermatogenesis in a polarized manner. To generate that polarity, a subset of pre-hub cells migrates through the germ cell milieu of the forming gonad, and undergoes a mesenchymal-to-epithelial transition (MET), only then acting as niche cells. Finally, the key self-renewal signal is delivered by BMPs expressed from both hub cells and CySCs. The first Aim uses a combination of live-imaging and loss- and gain-of-function studies to explore cytoskeletal control of pre-hub cell migration, and the mesenchymal-to-epithelial transition necessary for niche formation. A second Aim focuses on Zfh1, a transcriptional regulator which is key to CySC self- renewal and to how CySCs act as niche cells for GSC renewal. Targets of Zfh1 will be indentified and analyzed functionally. This will define genes important for CySC self- renewal, for the production of renewal signals for GSCs, and for the control of MET.

描述（由申请人提供）：人们对指导干细胞行为的电路非常感兴趣。虽然生态位对于许多组织特异性干细胞的行为至关重要，但目前尚不清楚生态位是如何在组织中指定和组装的，以及它如何对干细胞库进行控制。了解这些相互作用对于在再生医学中使用这些细胞至关重要。该提案解决了生态位如何指定、组织和发挥作用，并利用了最容易理解的干细胞生态位系统之一——果蝇睾丸。在这里，一小群细胞（中心细胞）充当生态位的一部分，导致相邻细胞中信号通路的激活。通过这种方式，附近的体细胞呈现囊肿干细胞命运（CySC），而附近的生殖细胞与这些CySC混合，呈现生殖系干细胞命运（GSC）。轮毂的形成以及随之而来的干细胞的附着是性腺发生的主要结构事件。体细胞性腺前体 (SGP) 中枢纽细胞的规范和放置产生了一个前锚定的增殖中心，它将以极化方式驱动精子发生。为了产生这种极性，前中心细胞的一个子集会迁移通过正在形成的性腺的生殖细胞环境，并经历间充质到上皮的转变（MET），然后才充当生态位细胞。最后，关键的自我更新信号由中枢细胞和 CySC 表达的 BMP 传递。第一个目标结合实时成像以及功能丧失和功能获得研究来探索中心前细胞迁移的细胞骨架控制，以及生态位形成所需的间充质到上皮的转变。第二个目标关注 Zfh1，它是一种转录调节因子，对于 CySC 自我更新以及 CySC 如何充当 GSC 更新的利基细胞至关重要。 Zfh1的目标将被识别并进行功能分析。这将定义对于 CySC 自我更新、GSC 更新信号的产生以及 MET 控制重要的基因。