Regulation of developing intestinal stem cells by unique secretory cells

摘要/摘要 脊椎动物的肠道在成体成熟之前经历了一系列共同的事件。 不同物种的比较表明，随着管子的形成，增殖发生在整个展开的 上皮组织。当上皮开始折叠时，上皮的增殖就被限制在底部。 发育中的褶皱(斑马鱼)和绒毛(老鼠)。由于增殖仅限于绒毛基底部，干细胞开始 形式。虽然发育中的干细胞表达一些成年干细胞的基因，但表达的是 显著降低，表明这些细胞是不成熟的。肠道干细胞还可以降低体内 当细胞外基质成分成熟时。而像Wnt这样的信号通路在驾驶中起着一定的作用 这些干细胞的增殖，可能会有新的信号和与独特细胞不同的相互作用 类型以完成未成熟干细胞的生长和成熟。关于未成熟的人的状态的细节 干细胞已经被研究过了，但对周围利基中的信号和细胞知之甚少 在成体干细胞形成之前调节生长。在本提案中，我们将调查这些角色 上皮细胞增殖调控中的新细胞类型以及它们如何与其他信号相互作用 限制增殖到干细胞生态位成熟之间的途径。在这里，我们使用 斑马鱼模型系统的外部开发和透明度的优势 转基因品系操作后干细胞生态位的发展。在目标1中，我们确定Notch如何 在调节上皮细胞增殖的过程中，信号与其他途径相互作用。在目标2中，我们将烧蚀细胞 通过接收Notch信号来分析它们在上皮细胞增殖中的作用。最后，在目标3中，我们将确定 哪些Notch受体参与这些信号事件。总之，这些研究将确定新的特征 控制未成熟干细胞的生长的信号网络，当它成熟到成体时。 了解调节细胞和信号在发育中的干细胞生态位中的作用将提供 关于干细胞生态位如何在不同组织和物种中发展的共性的信息。 了解这些共性将有助于培养新的干细胞或使老化的干细胞重新活跃起来。

Summary/Abstract The vertebrate intestine develops through a common series of events prior to maturation of the adult form. Comparison of different species reveals that as the tube forms, proliferation occurs throughout the unfolded epithelium. As the epithelium begins to fold, epithelial proliferation becomes restricted to the base of the developing folds (zebrafish) and villi (mouse). As proliferation is restricted to the villi base, stem cells begin to form. While the developing stem cells express some of the genes of their adult counterparts, expression is significantly lower suggesting that these cells are immature. Intestinal stem cells also decrease levels of extracellular matrix components as they mature. While signaling pathways such as Wnt play a role in driving proliferation of these stem cells, there is likely to be novel signaling and different interactions with unique cell types to complete growth and maturation of the immature stem cells. Details about the state of the immature stem cells has been investigated but less is known about signals and cells in the surrounding niche that regulate growth during the period before adult stem cells form. In this proposal, we will investigate the roles of novel cell types in regulation of epithelial proliferation and how they interact with other signaling pathways between restriction of proliferation to maturation of the stem cell niche. Here we use the advantages of external development and transparency of the zebrafish model system to visualize the developing stem cell niche following manipulation of transgenic lines. In Aim 1 we determine how Notch signaling interacts with other pathways in regulating epithelial proliferation. In Aim 2 we will ablate cells receiving Notch signaling to analyze their role in epithelial proliferation. Finally, in Aim 3 we will determine which Notch receptors participate in these signaling events. Together, these studies will identify new features of the network of signals controlling growth of the immature stem cell niche as it matures to the adult form. Understanding the role of regulatory cells and signals within the developing stem cell niche will provide information about the commonalities of how stem cell niches develop across different tissues and species. Understanding these commonalities will aid in approaches to grow new or reactivate aged stem cell niches.