The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary
The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary
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DOI：
10.1534/genetics.114.167346
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发表时间：
2014-11-01
期刊：
影响因子：
3.3
通讯作者：
Yu, Jenn-Yah
中科院分区：
文献类型：
--
作者：
Lin, Tzu-Huai;Yeh, Tsung-Han;Yu, Jenn-Yah
Hippo 通路是控制器官大小的关键信号级联。该通路的核心成分是两种激酶 Hippo (Hpo) 和 Warts (Wts) 以及转录共激活因子 Yorkie (Yki)。 Yes 相关蛋白（YAP，哺乳动物中的 Yki 同源物）在体外促进上皮间质转化和细胞迁移。在这里，我们使用果蝇卵巢中的边缘细胞作为模型来研究 Hippo 通路在体内细胞迁移中的功能。在卵子发生过程中，极细胞会分泌 Unpaired (Upd)，激活邻近细胞的 JAK/STAT 信号传导并将其指定为外缘细胞。外缘细胞与极细胞形成簇并进行迁移。我们发现 hpo 和 wts 是边界细胞簇迁移所必需的。在外缘细胞中，hpo 的过度表达会破坏肌动蛋白细胞骨架的极化并减弱迁移。在极性细胞中，hpo 和 wts 的敲低或 yki 的过度表达会损害边缘细胞诱导并破坏迁移。极细胞中的这些操作降低了外缘细胞中的 JAK/STAT 活性。 upd-lacZ 的表达在 yki 和 hpo 突变极细胞中分别增加和减少。此外，upd在极性细胞中的强制表达可以挽救由wts敲低引起的边缘细胞诱导和迁移的缺陷。这些结果表明，Yki 通过抑制 JAK/STAT 信号传导来负向调节边界细胞诱导。总之，我们的数据阐明了 Hippo 通路在控制边界细胞迁移方面的两种不同机制：（1）在外边界细胞中，它调节肌动蛋白细胞骨架的极化分布； (2)在极性细胞中，它调节upd表达以控制边缘细胞的诱导和迁移。
The Hippo pathway is a key signaling cascade in controlling organ size. The core components of this pathway are two kinases, Hippo (Hpo) and Warts (Wts), and a transcriptional coactivator, Yorkie (Yki). Yes-associated protein (YAP, a Yki homolog in mammals) promotes epithelial-mesenchymal transition and cell migration in vitro. Here, we use border cells in the Drosophila ovary as a model to study Hippo pathway functions in cell migration in vivo. During oogenesis, polar cells secrete Unpaired (Upd), which activates JAK/STAT signaling of neighboring cells and specifies them into outer border cells. The outer border cells form a cluster with polar cells and undergo migration. We find that hpo and wts are required for migration of the border cell cluster. In outer border cells, overexpression of hpo disrupts polarization of the actin cytoskeleton and attenuates migration. In polar cells, knockdown of hpo and wts or overexpression of yki impairs border cell induction and disrupts migration. These manipulations in polar cells reduce JAK/STAT activity in outer border cells. Expression of upd-lacZ is increased and decreased in yki and hpo mutant polar cells, respectively. Furthermore, forced expression of upd in polar cells rescues defects of border cell induction and migration caused by wts knockdown. These results suggest that Yki negatively regulates border cell induction by inhibiting JAK/STAT signaling. Together, our data elucidate two distinct mechanisms of the Hippo pathway in controlling border cell migration: (1) in outer border cells, it regulates polarized distribution of the actin cytoskeleton; (2) in polar cells, it regulates upd expression to control border cell induction and migration.