Matsuoka Shinya, Gupta Swati, Suzuki Emiko, Hiromi Yasushi, Asaoka Miho
Department of Developmental Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan; Department of Genetics, SOKENDAI, Mishima, Shizuoka, Japan.
Department of Developmental Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
PLoS One. 2014 Nov 24;9(11):e113423. doi: 10.1371/journal.pone.0113423. eCollection 2014.
In order to sustain lifelong production of gametes, many animals have evolved a stem cell-based gametogenic program. In the Drosophila ovary, germline stem cells (GSCs) arise from a pool of primordial germ cells (PGCs) that remain undifferentiated even after gametogenesis has initiated. The decision of PGCs to differentiate or remain undifferentiated is regulated by somatic stromal cells: specifically, epidermal growth factor receptor (EGFR) signaling activated in the stromal cells determines the fraction of germ cells that remain undifferentiated by shaping a Decapentaplegic (Dpp) gradient that represses PGC differentiation. However, little is known about the contribution of germ cells to this process. Here we show that a novel germline factor, Gone early (Goe), limits the fraction of PGCs that initiate gametogenesis. goe encodes a non-peptidase homologue of the Neprilysin family metalloendopeptidases. At the onset of gametogenesis, Goe was localized on the germ cell membrane in the ovary, suggesting that it functions in a peptidase-independent manner in cell-cell communication at the cell surface. Overexpression of Goe in the germline decreased the number of PGCs that enter the gametogenic pathway, thereby increasing the proportion of undifferentiated PGCs. Inversely, depletion of Goe increased the number of PGCs initiating differentiation. Excess PGC differentiation in the goe mutant was augmented by halving the dose of argos, a somatically expressed inhibitor of EGFR signaling. This increase in PGC differentiation resulted in a massive decrease in the number of undifferentiated PGCs, and ultimately led to insufficient formation of GSCs. Thus, acting cooperatively with a somatic regulator of EGFR signaling, the germline factor goe plays a critical role in securing the proper size of the GSC precursor pool. Because goe can suppress EGFR signaling activity and is expressed in EGF-producing cells in various tissues, goe may function by attenuating EGFR signaling, and thereby affecting the stromal environment.
为了维持配子的终身产生，许多动物进化出了基于干细胞的配子发生程序。在果蝇卵巢中，生殖系干细胞（GSCs）起源于一群原始生殖细胞（PGCs），这些原始生殖细胞即使在配子发生开始后仍保持未分化状态。PGCs分化或保持未分化的决定受体细胞基质细胞调控：具体而言，基质细胞中激活的表皮生长因子受体（EGFR）信号通过形成抑制PGC分化的Decapentaplegic（Dpp）梯度来决定保持未分化的生殖细胞比例。然而，关于生殖细胞对这一过程的贡献知之甚少。在这里，我们表明一种新的生殖系因子，早期消失（Goe），限制了启动配子发生的PGCs比例。goe编码一种中性肽链内切酶家族金属内肽酶的非肽酶同源物。在配子发生开始时，Goe定位于卵巢中的生殖细胞膜上，这表明它在细胞表面的细胞间通讯中以不依赖肽酶的方式发挥作用。在生殖系中过表达Goe会减少进入配子发生途径的PGCs数量，从而增加未分化PGCs的比例。相反，去除Goe会增加启动分化的PGCs数量。通过将体细胞表达的EGFR信号抑制剂argos的剂量减半，goe突变体中过量的PGC分化得到增强。PGC分化的这种增加导致未分化PGCs数量大幅减少，并最终导致GSCs形成不足。因此，生殖系因子goe与EGFR信号的体细胞调节因子协同作用，在确保GSC前体池的适当大小方面发挥关键作用。由于goe可以抑制EGFR信号活性并在各种组织中产生EGF的细胞中表达，goe可能通过减弱EGFR信号来发挥作用，从而影响基质环境。
