Control of Stem Cell Fate in Drosophila Spermatogenesis

摘要 成体干细胞通过不对称分裂再生组织，产生两种新的干细胞 和区分女儿。精原干细胞在体内提供终生精子供应 从苍蝇到人的各种生物。像所有生殖系干细胞一样，它们以独特的方式传递 基因组传给子孙后代。来自专门的局部微环境(或小生境)的信号 一般说来，干细胞是调节的，但在大多数组织中，利基很难识别和操纵 在活体内。一个例外是果蝇睾丸，它是干细胞生物学的领先模型。在……里面 这种组织，局部Janus-Kinase信号转导和转录激活因子(Jak-STAT) 信号传递促进干细胞在明确的生态位内更新，而细胞则离开该生态位 差异化。在我们之前的工作中，统计目标的特征使我们发现一个 单个干细胞可以获得一种突变，使其具有竞争优势：因此， 该细胞及其后代可以取代所有邻近的(野生型)干细胞。 随着时间的推移。这种现象被称为干细胞竞争，这一现象耐人寻味，但未经证实。 与人类生殖的联系。年龄较大的父亲生孩子的风险更高 由罕见的显性激活突变引起的遗传缺陷，如侏儒症 信号通路组件。尽管这些突变对后代有害，但它们确实是 被认为是老年男性的选择，因为他们提供单独的精原干细胞 电池是一种竞争优势。由于干细胞竞争尚未直接观察到 在目标1中，我们深入描述了这一过程 使用果蝇睾丸，它提供的遗传方法超过了 对哺乳动物的研究，应该能让我们对干细胞竞争有更全面的了解。在……里面 除了控制干细胞竞争，利基信号还确保干细胞在 成年果蝇的睾丸保持它们的“雄性”身份。性维持，这是茎的一种 细胞转分化，发生在哺乳动物身上，但机制尚不清楚。 因此，在目标2中，我们将全基因组的基因表达分析与遗传工具相结合 了解如何在体内调节性别维持是果蝇独有的。这将推动 再生医学领域，继续扩大我们对精原细胞的理解 干细胞--男性生殖的基石。

Abstract Adult stem cells regenerate tissue by dividing asymmetrically, producing both new stem cells and differentiating daughters. Spermatogonial stem cells provide a lifetime supply of sperm in organisms ranging from flies to man. Like all germline stem cells, they uniquely transmit the genome to future generations. Signals from specialized local microenvironments (or niches) regulate stem cells in general, but in most tissues niches are difficult to identify and manipulate in vivo. An exception is the Drosophila testis, which is a leading model for stem cell biology. In this tissue, local Janus-kinase-signal transducer and activator of transcription (Jak-STAT) signaling promotes stem cell renewal within a well-defined niche, while cells exiting the niche differentiate. In our prior work, characterization of STAT targets led us to discover that an individual stem cell can acquire a mutation that gives it a competitive advantage: as a result, that cell and its progeny can displace all of the neighboring (wild-type) stem cells from the niche over time. This phenomenon, called stem cell competition, has intriguing but unproven connections to human reproduction. Older fathers have a higher risk of having children with genetic defects such as dwarfism that are caused by rare, dominant activating mutations in signaling pathway components. Although the mutations are bad for the offspring, they are thought to be are selected for in aging men because they give individual spermatogonial stem cells a competitive advantage. Since stem cell competition has not been observed directly in mammals and is not understood mechanistically, in Aim 1 we characterize this process in depth using the Drosophila testis, which offers genetic approaches that surpass those available in mammals, and should inform the understanding of stem cell competition quite generally. In addition to controlling stem cell competition, niche signals also ensure that stem cells in the adult Drosophila testis maintain their “male” identity. Sex maintenance, which is a type of stem cell transdifferentiation, occurs in mammals but is not well understood mechanistically. Therefore, in Aim 2 we combine genome-wide analysis of gene expression with genetic tools unique to Drosophila to learn how sex maintenance is regulated in vivo. This will advance the field of regenerative medicine and continue to expand our understanding of spermatogonial stem cells - the cornerstone of male reproduction.