TRIP6透過YAP調控出生後小鼠側腦室-嗅球路逕上神經幹細胞的特性以及醫學上可能的應用

Abstract

出生後的哺乳動物腦中有持續的神經元新生，分別發生在海馬迴齒狀迴，以及側腦室下區到嗅球的路徑上。報導指出內生性的神經幹細胞有治療腦傷或神經退化性疾病的潛力，研究調控神經幹細胞的因子和機制因此有醫學上的應用價值。已知神經幹細胞的特性受到多種因子調控，然而TRIP6、YAP以及銀杏萃取物ginkgolide B等對於出生後哺乳動物神經幹細胞的影響仍是未知的。TRIP6的蛋白質結構具有三個LIM區位，可以和多種蛋白質進行交互作用而調控細胞增生、存活及移動。我們發現TRIP6不表現在會移動的神經母細胞中，而表現在神經幹細胞中。TRIP6促進神經幹細胞的維持、增生，並且抑制分化。且促進神經幹細胞自我更新的Notch訊息傳遞路徑能被TRIP6活化。Hippo訊息傳遞路徑藉由抑制YAP來調控細胞增生，控制器官大小。我們發現TRIP6透過PP1A來抑制Hippo訊息傳遞路徑，活化YAP。並且TRIP6透過YAP來促進神經幹細胞的維持、增生，以及抑制分化。在神經幹細胞的分化上，我們則發現ginkgolide B透過Wnt訊息傳遞路徑促進神經元新生。我們這一系列的研究指出TRIP6透過YAP維持神經幹細胞的特性，而給予ginkgolide B則可以促進神經元新生。

Postnatal neurogenesis in the dentate gyrus and subventricular zone (SVZ)-olfactory bulb pathway in mammals is regulated by extrinsic and intrinsic factors. Since endogenous neural stem cells (NSCs) in the adult brain have potential to treat neurodegenerative disorders, studying mechanisms regulating postnatal NSCs may provide clinical applications. However, the role of TRIP6, YAP and ginkgolide B in postnatal NSCs remain unclear. TRIP6 belongs to zyxin family of LIM proteins, which have been shown to interact with various proteins to regulate cell proliferation, survival and migration. We find that TRIP6 is expressed by adult NSCs in the SVZ but not migrating neuroblasts. TRIP6 is necessary and sufficient for self-renewal and proliferation of adult NSCs, but inhibits their differentiation. We also find that TRIP6 activates the Notch signaling, a pathway required for NSC self-renewal. Previous studies show that the Hippo pathway regulates cell proliferation and organ size through inhibiting YAP. We find that TRIP6 inhibits the Hippo pathway and activates YAP through PP1A. TRIP6 promotes NSC maintenance and proliferation and inhibits neuronal differentiation through YAP. During differentiation of NSCs, we also find that ginkgolide B promotes neurogenesis through the Wnt pathway. These findings show that YAP acts downstream of TRIP6 to promote adult NSC maintenance, whereas ginkgolide B promotes neurogenesis in the postnatal NSCs.