Regulation of developing intestinal stem cells by unique secretory cells

摘要/摘要 脊椎动物的肠在成体形式成熟之前通过一系列常见的事件发育。 不同物种的比较表明，随着管的形成，整个未折叠的 上皮当上皮开始折叠时，上皮增殖变得局限于基底部， 正在发育的褶皱（斑马鱼）和绒毛（小鼠）。由于增殖仅限于绒毛基底，干细胞开始 form.虽然发育中的干细胞表达成年干细胞的一些基因，但表达是不稳定的。 这表明这些细胞是不成熟的。肠干细胞还能降低 细胞外基质成分，因为它们成熟。虽然Wnt等信号通路在驱动 这些干细胞的增殖，可能存在新的信号传导和与独特细胞的不同相互作用。 干细胞的生长和成熟的关键。关于未成熟的状态的细节 干细胞已经被研究过，但对周围小生境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，我们将研究 新的细胞类型在调节上皮细胞增殖以及它们如何与其他信号相互作用 限制增殖与干细胞龛成熟之间的途径。这里我们使用 外部开发的优势和透明的斑马鱼模型系统，以可视化 在转基因系操作后形成干细胞龛。在目标1中，我们确定Notch如何 信号传导与调节上皮增殖的其它途径相互作用。在目标2中，我们将消融细胞 接收Notch信号以分析它们在上皮增殖中的作用。最后，在目标3中，我们将确定 哪些Notch受体参与了这些信号事件。总之，这些研究将确定新的特征， 控制未成熟干细胞小生境生长的信号网络，因为它成熟为成人形式。 了解调节细胞和信号在发育中的干细胞小生境中的作用， 关于干细胞小生境如何在不同组织和物种中发育的共性的信息。 了解这些共性将有助于培养新的或重新激活老化干细胞的方法。

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.