Mechanisms Controlling Epithelial Homeostasis

 描述（由申请人提供）：干细胞的长期维持和功能取决于局部干细胞微环境或小生境产生的信号。虽然在确定干细胞调节所需的利基因子方面取得了重大进展，但对控制干细胞对营养状态等系统性变化的反应的机制知之甚少。在果蝇卵巢中，生殖干细胞（GSCs）和卵泡干细胞（FSCs）在食物充足的情况下增殖活跃，但在营养有限的情况下增殖迅速受阻。最近，我们从分子水平上确定了将营养状态的变化转化为FSC增殖控制的机制。具体来说，我们发现，饮食胆固醇触发释放刺猬（Hh）分子螯合的Hh结合蛋白Boi的表面上的Hh生产细胞在卵巢内。由此产生的Hh配体在FSC龛中的积累驱动FSC增殖。这种机制使快速，组织特异性反应的全球变化的营养供应，从而定制卵巢干细胞分裂和卵子生产的环境条件下，是足够的后代生存。此外，我们的初步工作揭示了新的，轴突样细胞的FSC延伸的预测，其作用在一个整合素依赖的方式来定向FSC分裂和建立轨道的预测，定位FSC的女儿在利基。FSC预测接触子细胞和生殖细胞包囊，这表明FSC预测在FSC生态位内介导细胞类型之间的通信中的作用。与整联蛋白突变一样，FSC生态位内Hh信号水平的变化导致FSC投射的方向性、数量和长度的缺陷，这表明Hh信号在投射形态和维持的调节中起关键作用。基于这些结果，我们提出Hh在两步过程中将FSC分裂和卵产生量身定制为营养物质可用性的系统性变化，所述两步过程包括1）Boi介导的Hh螯合/释放和2）随后通过调节FSC投射动力学来调节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.