Mechanisms Controlling Epithelial Homeostasis

控制上皮稳态的机制

• 批准号: 9240655
• 负责人: Alana M O'Reilly
• 金额: $ 37.5万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-14 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240655
• 关键词: Affect; Apical; Axon; BCAR1 gene; Binding; Binding Proteins; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cholesterol; Communication; Cues; Cyst; Cytoplasmic Tail; Defect; Degenerative Disorder; Development; Diabetes Mellitus; Diet; Dietary Cholesterol; Dimerization; Disease; Distant; Drosophila genus; Epithelial; Erinaceidae; Event; Food; Genes; Genetic; Genetic Screening; Genetic Transcription; Germ Cells; Global Change; Goals; Homeostasis; Ingestion; Integrins; Lead; Length; Ligands; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Morphology; Mutation; Normal tissue morphology; Nutrient; Nutritional; Nutritional status; Organism; Ovarian; Ovarian Follicle; Ovary; Phosphorylation; Positioning Attribute; Premature aging syndrome; Process; Production; Proliferating; Proteins; Regulation; Repression; Ribosomal Protein S6 Kinase; Role; Signal Transduction; Somatic Cell; Stem cells; Surface; Testing; Tissues; Transcriptional Activation; Translating; Traumatic injury; Wing; Work; adult stem cell; base; cdc Genes; cell behavior; cell type; daughter cell; dimer; egg; feeding; fly; germline stem cells; novel; patched protein; prevent; public health relevance; receptor; response; smoothened signaling pathway; src-Family Kinases; stem cell division; stem cell niche; stem cell therapy

 DESCRIPTION (provided by applicant): The long term maintenance and function of stem cells depend on signals generated by the local stem cell microenvironment, or niche. While significant progress has been made in identifying the niche-generated factors necessary for stem cell regulation, little is known about the mechanisms that control stem cell responses to systemic changes such as nutritional status. In the fly ovary, germline stem cells (GSCs) and follicle stem cells (FSCs) proliferate actively in the presence of abundant food, but rapidly arres proliferation when nutrients are limited. Recently, we molecularly defined the mechanism that translates changes in nutrient status to FSC proliferation control. Specifically, we found that dietary cholesterol triggers release of Hedgehog (Hh) molecules sequestered by the Hh binding protein Boi on the surface of Hh-producing cells within the ovary. The resulting accumulation of Hh ligand in the FSC niche drives FSC proliferation. This mechanism enables a rapid, tissue-specific response to global changes in nutrient availability, thus tailoring ovarian stem cell divisions and egg production to environmental conditions that are sufficient for progeny survival. In addition, our preliminary work uncovers novel, axon-like cellular projections extended by FSCs that act in an integrin-dependent manner to orient FSC division and establish tracks of projections that position FSC daughters within the niche. FSC projections contact daughter cells and germline cysts, suggesting a role for FSC projections in mediating communication between cell types within the FSC niche. Like integrin mutation, changes in Hh signaling levels within the FSC niche lead to defects in the directionality, number, and length of FSC projections, suggesting a critical role for Hh signaling in regulation of projection morphology and maintenance. Based on these results, we propose that Hh tailors FSC divisions and egg production to systemic changes in nutrient availability in a two-step process that includes 1) Boi-mediated Hh sequestration/release and 2) subsequent regulation of communication between cells within the FSC niche via regulation of FSC projection dynamics.