Hippo Pathway Regulation of Vertebrate Ventricle Morphogenesis and Expansion

Hippo 通路对脊椎动物心室形态发生和扩张的调节

• 批准号: RGPIN-2016-04682
• 负责人: Waskiewicz, Andrew
• 金额: $ 2.77万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629051
• 关键词: Hippo; Pathway; Regulation; Vertebrate; Ventricle

During development, the vertebrate brain forms four cavities, known as ventricles, that serve as a secondary circulatory system, transporting nutrients and removing wastes from neural cells. The importance of the ventricular system is highlighted by consequences resulting from its maldevelopment. Schizencephaly (characterized by seizures and severe neurologic deficits) arises when fissures permit cerebrospinal fluid to leak out of the ventricles. Hydrocephalus (enlarged ventricles typically resulting from obstructed fluid flow) results in impaired neuronal number and cognitive impairment. Given its critical function, it is surprising that we lack a complete understanding of the mechanisms that control development of the vertebrate brain ventricular system. On the basis of studies in zebrafish and mouse, we know that brain ventricle formation is critically dependent on correct apico-basal cell polarity and regulated proliferation/apoptosis. Yet, the signaling pathways that regulate these processes remain only partially characterized. We reasoned that Hippo signaling, given its roles in other tissues in regulating polarity and proliferation, would be an excellent candidate regulator of brain ventricle formation. We utilized TALEN mutagenesis to create a zebrafish strain lacking Taz, a transcription co-activator regulated by Hippo signaling. Zebrafish

在发育过程中，脊椎动物的大脑形成四个被称为脑室的空腔，作为第二循环系统，运输营养物质并从神经细胞中清除废物。脑室系统发育不良所造成的后果凸显了它的重要性。脑裂畸形(以癫痫发作和严重的神经功能障碍为特征)发生在脑裂使脑脊液从脑室漏出时。脑积水(脑室扩大通常是由于液体流动受阻引起的)会导致神经元数量受损和认知障碍。鉴于其关键功能，令人惊讶的是，我们对脊椎动物脑室系统发育的控制机制缺乏完整的了解。在斑马鱼和小鼠的研究基础上，我们知道脑室的形成关键依赖于正确的顶基细胞极性和调节的增殖/凋亡。然而，调控这些过程的信号通路仍然只有部分特征。我们认为，考虑到河马信号在其他组织中调节极性和增殖的作用，它将是脑室形成的一个很好的候选调节器。我们利用TALEN突变创造了一个缺少Taz的斑马鱼品系，Taz是一种受河马信号调节的转录辅助激活因子。斑马鱼