Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Cell. 2010 Dec 10;143(6):978-90. doi: 10.1016/j.cell.2010.11.022.
In the Drosophila ovary, germline stem cells (GSCs) are maintained primarily by bone morphogenetic protein (BMP) ligands produced by the stromal cells of the niche. This signaling represses GSC differentiation by blocking the transcription of the differentiation factor Bam. Remarkably, bam transcription begins only one cell diameter away from the GSC in the daughter cystoblasts (CBs). How this steep gradient of response to BMP signaling is formed has been unclear. Here, we show that Fused (Fu), a serine/threonine kinase that regulates Hedgehog, functions in concert with the E3 ligase Smurf to regulate ubiquitination and proteolysis of the BMP receptor Thickveins in CBs. This regulation generates a steep gradient of BMP activity between GSCs and CBs, allowing for bam expression on CBs and concomitant differentiation. We observed similar roles for Fu during embryonic development in zebrafish and in human cell culture, implying broad conservation of this mechanism.
在果蝇卵巢中，生殖干细胞（GSCs）主要由巢基质细胞产生的骨形态发生蛋白（BMP）配体维持。这种信号通过阻止分化因子 Bam 的转录来抑制 GSC 分化。值得注意的是，bam 转录仅在距离 GSC 一个细胞直径的子囊胚细胞（CBs）中开始。BMP 信号的这种陡峭梯度响应是如何形成的尚不清楚。在这里，我们表明，调节 Hedgehog 的丝氨酸/苏氨酸激酶 Fused（Fu）与 E3 连接酶 Smurf 协同作用，调节 CBs 中 BMP 受体 Thickveins 的泛素化和蛋白水解。这种调节在 GSCs 和 CBs 之间产生了 BMP 活性的陡峭梯度，允许在 CBs 上表达 bam 并伴随分化。我们在斑马鱼胚胎发育和人细胞培养中观察到 Fu 具有类似的作用，这意味着这种机制具有广泛的保守性。
