Hippo Pathway Regulation of Vertebrate Ventricle Morphogenesis and Expansion

在发育过程中，脊椎动物的大脑形成了四个腔，称为脑室，作为二级循环系统，运输营养物质并从神经细胞中清除废物。心室系统发育不良的后果突出了它的重要性。脑裂症（以癫痫发作和严重的神经功能缺陷为特征）发生时，脑脊液从脑室泄漏。脑积水（脑室增大，通常是由于流体流动受阻）导致神经元数量减少和认知障碍。考虑到脑室系统的关键功能，令人惊讶的是，我们对控制脊椎动物脑室系统发育的机制缺乏完整的了解。根据斑马鱼和小鼠的研究，我们知道脑室的形成严重依赖于正确的顶基底细胞极性和调节的增殖/凋亡。然而，调节这些过程的信号通路仍然只是部分表征。我们推断，鉴于Hippo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极好的候选调节因子。我们利用TALEN诱变技术创造了一个缺乏Taz的斑马鱼品系，Taz是一种由Hippo信号调节的转录共激活因子。斑马鱼

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