Loss of lysine-specific demethylase 1 nonautonomously causes stem cell tumors in the Drosophila ovary
Loss of lysine-specific demethylase 1 nonautonomously causes stem cell tumors in the Drosophila ovary
复制标题
DOI：
10.1073/pnas.1015874108
复制
发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Buszczak, Michael
中科院分区：
文献类型：
--
作者：
Eliazer, Susan;Shalaby, Nevine A.;Buszczak, Michael
被称为小生境的特殊微环境使干细胞保持在未分化和自我更新的状态。专用的基质细胞通过产生直接作用于干细胞的各种因子形成小生境。小生境的大小和信号输出必须微调，以确保适当的组织稳态。虽然在确定促进小生境细胞命运的因素方面取得了进展，但在发育过程中限制小生境细胞形成和限制成年人小生境信号输出的机制仍然知之甚少。在这里，我们表明，组蛋白赖氨酸特异性去甲基化酶1（Lsd1）调节果蝇卵巢的生殖系干细胞（GSC）龛的大小。GSC的维持依赖于位于生殖器前端的一小群帽细胞产生的骨形态发生蛋白（BMP）信号。Lsd1无效突变卵巢携带小的生殖系肿瘤，其中含有大量的GSC样细胞，这些细胞具有圆形融合体，显示异位BMP信号反应远离正常小生境。克隆分析和细胞类型特异性救援实验表明，Lsd1功能的护送细胞（EC），居住在紧邻帽细胞，并防止它们异位产生利基特异性信号。时间限制的基因敲除实验表明，Lsd1功能在发展过程中，指定EC的命运，并在成年期，以防止EC形成异位壁龛独立于细胞命运的变化。进一步的分析表明，Lsd1的功能，以抑制decapentaplegic（dpp）的表达，在成年germaria。Lsd1在调节生态位特异性信号中的作用可能对理解其哺乳动物同源物的破坏如何导致癌症和转移具有重要意义。
Specialized microenvironments called niches keep stem cells in an undifferentiated and self-renewing state. Dedicated stromal cells form niches by producing a variety of factors that act directly on stem cells. The size and signaling output of niches must be finely tuned to ensure proper tissue homeostasis. Although advances have been made in identifying factors that promote niche cell fate, the mechanisms that restrict niche cell formation during development and limit niche signaling output in adults remain poorly understood. Here, we show that the histone lysine-specific demethylase 1 (Lsd1) regulates the size of the germline stem cell (GSC) niche in Drosophila ovaries. GSC maintenance depends on bone morphogenetic protein (BMP) signals produced by a small cluster of cap cells located at the anterior tip of the germarium. Lsd1 null mutant ovaries carry small germline tumors containing an expanded number of GSC-like cells with round fusomes that display ectopic BMP signal responsiveness away from the normal niche. Clonal analysis and cell type-specific rescue experiments demonstrate that Lsd1 functions within the escort cells (ECs) that reside immediately adjacent to cap cells and prevents them from ectopically producing niche-specific signals. Temporally restricted gene knockdown experiments suggest that Lsd1 functions both during development, to specify EC fate, and in adulthood, to prevent ECs from forming ectopic niches independent of changes in cell fate. Further analysis shows that Lsd1 functions to repress decapentaplegic (dpp) expression in adult germaria. The role of Lsd1 in regulating niche-specific signals may have important implications for understanding how disruption of its mammalian homolog contributes to cancer and metastasis.