Function & regulation of Hippo pathway effectors YAP/TAZ during brain development

描述（由申请人提供）：神经干细胞/祖细胞在神经发育过程中发挥关键作用。它们作为所有神经元和神经胶质的来源，并有助于神经系统形成的组织发生过程。阐明控制神经前体细胞特性和功能的分子机制不仅对理解神经前体细胞的功能至关重要， 发育以及由神经祖细胞失调和功能障碍引起的人类疾病。本申请的目的是研究哺乳动物脑发育过程中一种新的信号传导途径Hippo途径的功能。通过调节转录辅激活因子雅普及其辅因子TAZ的活性，Hippo途径控制几种哺乳动物器官的发育、稳态和/或肿瘤发生。然而，它在哺乳动物大脑发育中的作用在很大程度上是未知的。我们的实验室最近表明，异常的雅普激活导致神经祖细胞群的过度扩张，并且神经纤维瘤病2型（NF 2）肿瘤抑制剂Merlin是脑发育过程中雅普/TAZ的生理抑制剂。此外，我们还发现Merlin和雅普在调节胼胝体（大脑两半球之间最大的连合连接）的形成方面具有新的功能。本研究的总体目标是阐明Merlin和雅普/TAZ调控脑发育的分子机制。具体而言，拟议的研究将：（1）确定Merlin调节雅普的生化机制，（2）确定Merlin-雅普级联调节胼胝体形成的分子机制，以及（3）定义雅普/TAZ调节神经祖细胞特性的转录程序。这项研究将有助于阐明雅普/TAZ在脑发育过程中的作用，并扩展我们对神经祖细胞行为调控机制的认识。它还将阐明NF 2/Merlin肿瘤抑制因子的生理功能和作用机制，并深入了解人类NF 2突变如何导致或促进肿瘤发生。最后，它将揭示一种新的信号级联，调节轴突的指导，并提供新的见解的机制背后的胼胝体畸形，这是在出生时发现的最常见的大脑异常。

DESCRIPTION (provided by applicant): Neural stem/progenitor cells play critical roles during neural development. They serve as the source of all neurons and glia and contribute to the histogenetic processes of nervous system formation. Elucidating the molecular mechanisms governing neural progenitor cell properties and functions is critical to understand not only neural development but also human diseases caused by neural progenitor dysregulation and malfunction. The objective of this application is to investigate the function of a novel signaling pathway, the Hippo pathway, during mammalian brain development. By regulating the activity of the transcriptional coactivators YAP and its paralog TAZ, the Hippo pathway controls the development, homeostasis, and/or tumorigenesis of several mammalian organs. However, its role during mammalian brain development is largely unknown. Our laboratory recently showed that aberrant YAP activation causes overexpansion of the neural progenitor population and that the neurofibromatosis type-2 (NF2) tumor suppressor Merlin is a physiological inhibitor of YAP/TAZ during brain development. Moreover, we discovered a novel function of Merlin and YAP in regulating the formation of the corpus callosum, the largest commissural connection between the cerebral hemispheres. The overall goal of this proposal is to elucidate the molecular mechanism by which Merlin and YAP/TAZ regulate brain development. Specifically, the proposed study will: (1) determine the biochemical mechanism by which Merlin regulates YAP, (2) determine the molecular mechanism through which the Merlin-YAP cascade regulates corpus callosum formation, and (3) define the transcriptional program through which YAP/TAZ regulate neural progenitor properties. The proposed study is expected to define the function of YAP/TAZ during brain development and expand our knowledge on mechanisms regulating neural progenitor behaviors. It will also elucidate the physiological function and mechanism of action of the NF2/Merlin tumor suppressor and provide insight into how NF2 mutations in humans cause or contribute to tumorigenesis. Lastly, it will uncover a novel signaling cascade that regulates axon guidance and provide new insight into the mechanisms underlying callosal malformations, which are among the most common brain anomalies found at birth.