Maintenance of Stem Cell Fates in Drosophila

果蝇干细胞命运的维持

• 批准号: 7903101
• 负责人: EDWIN L FERGUSON
• 金额: $ 28.44万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903101
• 关键词: Adherens Junction; Adhesions; Anterior; Antibodies; Attention; Biosensor; Blood; Bone Morphogenetic Proteins; Cell Maintenance; Cell physiology; Cells; Characteristics; Complex; Data; Daughter; Disease; Drosophila genus; Drosophila melanogaster; Ensure; Environment; Family member; Feedback; Female; Genes; Genetic; Genetic Transcription; Germ Lines; Hair; Healed; Histocompatibility Testing; Homeostasis; Homologous Gene; Injury; Knowledge; Left; Life; Ligands; MAPK8 gene; Maintenance; Molecular; Monomeric GTP-Binding Proteins; Morphology; Mutation; Neurons; Nuclear; Oocytes; Pathway interactions; Pattern; Phenotype; Protein Family; Proteins; Receptor Activation; Role; Series; Signal Transduction; Sister; Skin; Stem cells; System; Testing; Therapeutic; Tissues; Transducers; Undifferentiated; adult stem cell; base; bone morphogenetic protein receptors; design; extracellular; healing; in vivo; insight; member; receptor internalization; research study; response; self-renewal; stem cell differentiation; stem cell division; stem cell fate; stem cell niche; uptake

DESCRIPTION (provided by applicant): The asymmetric self-renewal divisions of adult stem cells underlie the continued homeostasis of many tissues of the body. Most, if not all, stem cells are present in a microenvironment, called a niche that provides three conditions necessary for long-term stem cell maintenance. Adhesion between the niche cell and the stem cell anchors the stem cell within the niche. Intercellular signals from the niche maintain the stem cell in an undifferentiated state. Lastly, the niche has the capability to set up an intrinsic polarity within the stem cell to aid its asymmetric self-renewal divisions. An understanding of these interactions in an in vivo environment is essential prior to the use of stem cells for therapeutic purposes. The female germ line of the fruit fly Drosophila melanogaster is one of the preeminent systems for the study of stem cell niche interactions. The Germline Stem Cells (GSCs) are located at the anterior tip of each ovariole, adjacent to somatic cap cells that form the niche. Each GSC divides with an invariant plane of division to produce one daughter that stays in the niche and remains a GSC and a second daughter, a Cystoblast (CB), which leaves the niche and ultimately produces an oocyte. The GSCs are anchored to the cap cells by adherens junctions. Moreover, Bone Morphogenetic Protein (BMP) family members act as intercellular signals necessary for GSC maintenance. BMP signaling is high in GSCs, low in CBs, and absent from all CB progeny. This proposal tests the hypothesis that interactions between the cap cells and the GSCs set up an intrinsic polarity within the GSC that is manifest as an asymmetric activation of the small GTPase Rac at the GSC cap cell interface. Preliminary data suggest that locally activated Rac both controls the plane of division of the GSC and promotes BMP signaling within the GSC. The three specific aims in the proposal are designed to provide a molecular framework to understand how a cellular asymmetry within a stem cell can cooperate with an extracellular signal required for stem cell maintenance to ensure the robust pattern of asymmetric self-renewal divisions necessary for continued stem cell maintenance. These data should provide an intellectual framework to examine the mechanisms underlying the self-renewal divisions of vertebrate adult stem cells. Project Narrative. A stem cell normally divides to produce one cell like itself and one cell that differentiates into a particular tissue type, such as blood, skin or hair. The proposal seeks to understand how the interaction between a stem cell and its surrounding environment can influence the pattern of stem cell division. This knowledge could be very useful in attempts to use stem cells to heal injury or cure disease.

描述（由申请人提供）：成年干细胞的不对称自我更新分裂是人体许多组织的持续稳态。大多数（即使不是全部）干细胞存在于微环境中，称为一个利基市场，可提供长期干细胞维持所需的三种条件。小众细胞和干细胞之间的粘附锚定在小众内部的干细胞。来自利基市场的细胞间信号将干细胞保持在未分化状态。最后，利基市场有能力在干细胞内建立固有的极性，以帮助其不对称的自我更新分裂。在将干细胞用于治疗目的之前，必须了解体内环境中这些相互作用。果蝇果蝇的雌性生殖系是研究干细胞相互作用的杰出系统之一。种系干细胞（GSC）位于每个卵巢的前端，毗邻形成生态位的体细胞细胞。每个GSC都用一个不变的划分平面划分，生产一个女儿，该女儿留在利基市场中，并且仍然是GSC和第二个女儿，一个囊肿细胞（CB），该女儿离开了利基市场并最终产生了卵母细胞。 GSC被粘附连接固定在盖细胞上。此外，骨形态发生蛋白（BMP）家庭成员充当GSC维持所需的细胞间信号。 BMP信号在GSC中较高，CBS低，并且所有CB后代不存在。该建议检验了以下假设：在GSC中，Cap细胞与GSC之间的相互作用在GSC帽细胞界面上建立了GSC中的内在极性。初步数据表明，局部激活的RAC都控制了GSC的划分平面并促进GSC中的BMP信号传导。该提案中的三个特定目的旨在提供一个分子框架，以了解干细胞中的细胞不对称如何与干细胞维持所需的细胞外信号合作，以确保持续干细胞维持所需的不对称自我更新分裂的强大模式。这些数据应提供一个智力框架，以检查脊椎动物成年干细胞自我更新划分的基础机制。 项目叙述。 干细胞通常会分裂以产生一个像自身的细胞，一个细胞分化为特定组织类型，例如血液，皮肤或头发。该提案试图了解干细胞及其周围环境之间的相互作用如何影响干细胞分裂的模式。这些知识对于尝试使用干细胞治愈损伤或治愈疾病可能非常有用。