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

功能

基本信息

批准号：
9250224
负责人：
Xinwei Cao
金额：
$ 38.28万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9250224
关键词：
Behavior Binding Biochemical Biological Assay Biological Models Birth Brain Cell Death Cell Proliferation Cell Survival Cell physiology Cellular biology Cerebral hemisphere Complex Corpus Callosum Cues Cytoplasm Defect Development Diagnosis Etiology Gene Targeting Genetic Genetic Transcription Goals Growth Homeostasis Human In Vitro Knockout Mice Knowledge Laboratories Light Malignant Neoplasms Mechanics Modeling Molecular Mutant Strains Mice Mutation Nervous system structure Neural tube Neurofibromatosis 2 Neurofibromin 2 Neuroglia Neurons Organ Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiological Physiology Play Population Prevention Process Property Regulation Role Signal Pathway Signal Transduction Source Stem cells Structure Testing Tissues Transcript Transcription Coactivator Transcriptional Regulation Tumor Suppressor Proteins Up-Regulation axon guidance cell behavior cell type gain of function histogenesis human disease improved in vivo inhibitor/antagonist insight loss of function malformation mouse model mutant mutant mouse model nerve stem cell nervous system disorder neurodevelopment novel overexpression paralogous gene progenitor programs promoter public health relevance relating to nervous system self-renewal stem tissue/cell culture tumorigenesis

项目摘要

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.

描述（申请人提供）：神经干细胞/祖细胞在神经发育过程中起关键作用。它们是所有神经元和神经胶质的来源，并参与神经系统形成的组织发生过程。阐明控制神经祖细胞特性和功能的分子机制不仅对理解神经系统疾病至关重要