Genetic control of Drosophila intestine stem cell self-renewal and proliferation

摘要 在成年期，许多器官依靠干细胞通过补充丢失的细胞来维持其完整性 在组织内稳态期间或响应于损伤。成体干细胞的增殖和分化 在严格控制下，以实现去除死细胞和 产生新的细胞。基础监管机制的破坏可能会导致过度的 干细胞/祖细胞增殖，导致肿瘤形成。果蝇成虫的中肠 作为一个有吸引力的模型，研究干细胞增殖，自我更新和 分化受到调控，不仅是因为这种组织中的细胞谱系相对简单， 定义，但也因为保守的遗传途径和调控机制在这一过程中被利用。 与哺乳动物系统相比。此外，复杂的遗传工具和丰富的 果蝇群落中可用的试剂允许系统识别和深入研究 肠干细胞（ISC）生物学中涉及的基因和途径的表征。近年来， 我们已经证明，组织损伤刺激果蝇ISC增殖和分化， 中肠我们已经确定胰岛素和Hippo（Hpo）信号通路是两个关键通路， 调节中肠的体内平衡和再生。由于这一系统相对较新，我们的 对ISC生物学的理解仍然是初步的。例如，茎的细胞和分子基础 中肠的细胞龛仍然是虚幻的。这项研究的目的是确定新的遗传和 控制果蝇中肠稳态和再生的分子成分， 控制ISC自我更新和增殖的调节机制。为此，我们 启动了基因筛选，并确定了骨形态发生蛋白（BMP）的成分， 刺猬（Hh）途径对于中肠再生至关重要。我们将研究BMP的功能 和Hh途径在正常组织中调控ISC自我更新和增殖 稳态和损伤诱导再生。我们还将确定涉及的其他监管因素 在中肠内环境稳定和再生中的作用。该提案的具体目标是：1）调查 BMP信号通路在ISC自我更新调控中的作用及机制; 2）研究BMP信号通路在ISC自我更新调控中的作用， BMP信号的调节及其与中肠再生中其他途径的相互作用; 3） 研究Hh信号在中肠稳态和再生中的作用; 4）鉴定和 描述参与中肠再生的新基因。拟议的研究应提供更好的 了解外在信号和内在因素如何控制干细胞增殖、自我更新 以及成体组织稳态和再生过程中的分化。从中获得的知识 这项研究将对癌症生物学和再生医学产生重要影响。

Abstract During adult life, many organs rely on stem cells to maintain their integrity by replenishing lost cells during tissue homeostasis or in response to injury. Proliferation and differentiation of adult stem cells are under tight control in order to achieve the normal balance between removing dead cells and producing new cells. Disruption of the underlying regulatory mechanisms could result in excessive proliferation of stem cells/progenitor cells, leading to tumor formation. The Drosophila adult midgut has emerged as an attractive model to investigate how stem cell proliferation, self-renewal and differentiation are regulated, not only because the cell lineage in this tissue is relatively simple and well defined, but also because conserved genetic pathways and regulatory mechanisms are utilized in this system compared with mammalian systems. In addition, sophisticated genetic tools and the wealth of reagents available in the Drosophila community allow systematic identification and in-depth characterization of genes and pathways involved in intestine stem cell (ISC) biology. In recent years, we have demonstrated that tissue damage stimulates ISC proliferation and differentiation in Drosophila midgut. We have identified Insulin and Hippo (Hpo) signaling pathways as two critical pathways that regulate midgut homeostasis and regeneration. Because this system is relatively new, our understanding of ISC biology is still rudimentary. For example, the cellular and molecular basis of stem cell niche in the midgut has remained illusive. The goal of this research is to identify new genetic and molecular components that control Drosophila midgut homeostasis and regeneration with an emphasis on the regulatory mechanisms that control ISC self-renewal and proliferation. Toward this end, we have initiated a genetic screen and identified components in the Bone Morphogenic Protein (BMP) and Hedgehog (Hh) pathways as essential for midgut regeneration. We will investigate the function of BMP and Hh pathways in the regulation of ISC self-renewal and proliferation during normal tissue homeostasis and damage-induced regeneration. We will also identify other regulatory factors involved in midgut homeostasis and regeneration. The specific aims for this proposal are: 1) investigate the function and mechanism of BMP signaling in the regulation of ISC self-renewal; 2) investigate the regulation of BMP signaling and its interaction with other pathways in midgut regeneration; 3) investigate the role of Hh signaling in midgut homeostasis and regeneration; 4) identify and characterize new genes involved in midgut regeneration. The proposed study should provide better understanding of how extrinsic signals and intrinsic factors control stem cell proliferation, self-renewal and differentiation during adult tissue homeostasis and regeneration. The knowledge gained from this study will have important implications for cancer biology and regenerative medicine.