Mechanisms Controlling Epithelial Homeostasis

 描述(申请人提供)：干细胞的长期维持和功能取决于当地干细胞微环境或生态位产生的信号。虽然在确定干细胞调控所需的生态位生成因子方面取得了重大进展，但对控制干细胞对营养状况等系统性变化的反应的机制知之甚少。在果蝇卵巢中，生殖系干细胞(GSCs)和卵泡干细胞(FSCs)在食物丰富的情况下增殖活跃，但在营养物质有限的情况下迅速增殖。最近，我们从分子上定义了将营养状态的变化转化为FSC增殖控制的机制。具体地说，我们发现饮食中的胆固醇会触发Hedgehog(HH)分子的释放，HH结合蛋白Boi隔离在卵巢内HH产生细胞的表面。由此导致的HH配体在FSC利基中的积累推动了FSC的增殖。这种机制能够对全球营养供应的变化做出快速的、特定于组织的反应，从而使卵巢干细胞分裂和卵子生产适应足以保证后代存活的环境条件。此外，我们的初步工作揭示了FSCs延伸的新颖的轴突样细胞投射，这些投射以整合素依赖的方式定位FSC分裂，并建立定位FSC子代的投射轨迹。FSC投射接触子代细胞和生殖系包囊，表明FSC投射在调节FSC生态位内不同细胞类型之间的沟通中发挥作用。与整合素突变一样，FSC小生境内HH信号水平的变化会导致FSC投射的方向性、数量和长度方面的缺陷，这表明HH信号在调节投射形态和维持方面发挥了关键作用。基于这些结果，我们认为，HH通过一个两步过程来调整FSC的分裂和产卵，以适应营养可获得性的系统性变化，其中包括1)Boi介导的HH的封存/释放和2)随后通过调节FSC投射动态来调节FSC生态位内细胞之间的通信。

 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.