miR-285-Yki/Mask double-negative feedback loop mediates blood-brain barrier integrity in Drosophila
miR-285-Yki/Mask double-negative feedback loop mediates blood-brain barrier integrity in Drosophila
复制标题
miR-285→Yki/Mask双负反馈环介导果蝇血脑屏障完整性
DOI：
10.1073/pnas.1613233114
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发表时间：
2017-03-21
影响因子：
11.1
通讯作者：
Bi, Xiaolin
中科院分区：
文献类型：
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作者：
Li, Dong;Liu, Yanling;Bi, Xiaolin
Hippo 信号通路从果蝇到哺乳动物都高度保守，在维持器官大小和组织稳态方面发挥着核心作用。血脑屏障（BBB）在生理上将大脑与循环血液或血淋巴系统隔离，并严格维持其完整性以执行复杂的神经元功能。到目前为止，神经束膜下胶质细胞（SPG）生长和发育过程中血脑屏障维持的潜在机制尚不清楚。在这里，我们报告了一个 miR-285-Yorkie (Yki)/多个锚蛋白重复单 KH 结构域 (Mask) 双负反馈环，可调节 SPG 生长和 BBB 完整性。 miR-285 缺失的果蝇具有 BBB 缺陷，SPG 倍性增加和隔膜连接破坏。从机制上讲，miR-285 直接靶向 Yki 辅因子 Mask 来抑制 Yki 活性，并下调其下游靶细胞周期蛋白 E（细胞周期的关键调节因子）的表达。 SPG 中细胞周期蛋白 E 表达的干扰会导致异常的内复制，从而导致异常的 DNA 倍体和有缺陷的隔膜连接。此外，miR-285的表达通过yki或mask的敲低而增加，并随着yki的过表达而减少，从而形成双负反馈环。该调节环对于维持适当的 Yki/Mask 活性和细胞周期蛋白 E 水平以维持 SPG 倍性和 BBB 完整性至关重要。通过 miR-285 表达失调或 Yki 活性对该信号环路的扰动，会导致不规则的 SPG 倍性和 BBB 破坏。此外，miR-285 的异位表达促进典型 Hippo 通路介导的细胞凋亡，不依赖于 p53 或 JNK 通路。总的来说，这些结果揭示了通过 miR-285-Yki/Mask 调节电路维持 BBB 的精细调节机制。
The Hippo signaling pathway is highly conserved from Drosophila to mammals and plays a central role in maintaining organ size and tissue homeostasis. The blood-brain barrier (BBB) physiologically isolates the brain from circulating blood or the hemolymph system, and its integrity is strictly maintained to perform sophisticated neuronal functions. Until now, the underlying mechanisms of subperineurial glia (SPG) growth and BBB maintenance during development are not clear. Here, we report an miR-285-Yorkie (Yki)/Multiple Ankyrin repeats Single KH domain (Mask) double-negative feedback loop that regulates SPG growth and BBB integrity. Flies with a loss of miR-285 have a defective BBB with increased SPG ploidy and disruptive septate junctions. Mechanistically, miR-285 directly targets the Yki cofactor Mask to suppress Yki activity and down-regulates the expression of its downstream target cyclin E, a key regulator of cell cycle. Disturbance of cyclin E expression in SPG causes abnormal endoreplication, which leads to aberrant DNA ploidy and defective septate junctions. Moreover, the expression of miR-285 is increased by knockdown of yki or mask and is decreased with yki overexpression, thus forming a double-negative feedback loop. This regulatory loop is crucial for sustaining an appropriate Yki/Mask activity and cyclin E level to maintain SPG ploidy and BBB integrity. Perturbation of this signaling loop, either by dysregulated miR-285 expression or Yki activity, causes irregular SPG ploidy and BBB disruption. Furthermore, ectopic expression of miR-285 promotes canonical Hippo pathway-mediated apoptosis independent of the p53 or JNK pathway. Collectively, these results reveal an exquisite regulatory mechanism for BBB maintenance through an miR-285-Yki/Mask regulatory circuit.