A collection of 90 miRNA mutant lines.

The signaling environment, or niche, often governs the initial difference in behavior of an adult stem cell and a derivative that initiates a path towards differentiation. The transition between an instructive stem cell niche and differentiation niche must generally have single-cell resolution, suggesting that multiple mechanisms might be necessary to sharpen the transition. Here, we examined the Drosophila ovary and found that Cap cells, which are key constituents of the germline stem cell (GSC) niche, express a conserved microRNA (miR-124). Surprisingly, loss of miR-124 activity in Cap cells leads to a defect in differentiation of GSC derivatives. We present evidence that the direct functional target of miR-124 in Cap cells is the epidermal growth factor receptor (EGFR) and that failure to limit EGFR expression leads to the ectopic expression of a key anti-differentiation BMP signal in neighboring somatic escort cells (ECs), which constitute a differentiation niche. We further found that Notch signaling connects EFGR activity in Cap cells to BMP expression in ECs. We deduce that the stem cell niche communicates with the differentiation niche through a mechanism that begins with the selective expression of a specific microRNA and culminates in the suppression of the major anti-differentiation signal in neighboring cells, with the functionally important overall role of sharpening the spatial distinction between self-renewal and differentiation environments.

信号微环境（或称生态位）通常决定了成体干细胞与启动分化路径的子代细胞之间的初始行为差异。指导性干细胞微环境与分化微环境之间的转换通常需要单细胞分辨率，这提示可能需要多种机制来锐化该转换过程。本研究以果蝇卵巢为研究模型，发现作为生殖系干细胞（GSC）微环境关键组成部分的帽细胞（Cap cells），可表达一种保守的微小RNA（miR-124）。令人意外的是，帽细胞中miR-124活性缺失会导致GSC子代的分化缺陷。我们的研究证据表明，miR-124在帽细胞中的直接功能靶标为表皮生长因子受体（EGFR）；若无法限制EGFR的表达，会导致邻近构成分化微环境的体细胞护送细胞（ECs）异常表达关键的抗分化骨形态发生蛋白（BMP）信号。我们进一步发现，Notch信号通路可将帽细胞中的EGFR活性与ECs中的BMP表达关联起来。综上，我们推测干细胞微环境通过以下机制与分化微环境进行通信：首先选择性表达特定微小RNA，最终抑制邻近细胞中的主要抗分化信号，其核心功能在于锐化自我更新与分化微环境之间的空间边界。