Role of c-Jun N-terminal kinase signaling in cortical interneuron migration

c-Jun N-末端激酶信号在皮质中间神经元迁移中的作用

基本信息

批准号：
8887436
负责人：
ERIC S TUCKER
金额：
$ 32.59万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887436
关键词：
Autistic Disorder Automobile Driving Behavior Binding Proteins Biosensor Birth Place Brain Diseases Catastrophic Illness Cell physiology Cells Cerebral cortex Complex Cues Data Decision Making Development Disease Embryonic Development Epilepsy Etiology Event Functional disorder Genetic Genetic Predisposition to Disease Imaging Techniques Immigration In Situ Interneurons Invaded Knowledge Lateral Lead Light MAPK8 gene Mediating Mediator of activation protein Mental disorders Microtubules Molecular Molecular and Cellular Biology Mood Disorders Mus N-terminal Nervous system structure Neurologic Neurons Pathologic Phosphorylation Phosphotransferases Play Process Prosencephalon Publishing Refractory Risk Role Schizophrenia Signal Pathway Signal Transduction Source Stream Testing Time Travel Work cell motility developmental disease expectation extracellular genetic regulatory protein in vivo inhibitor/antagonist insight migration nervous system disorder neurodevelopment neuropsychiatry novel prenatal public health relevance response tool

项目摘要

DESCRIPTION (provided by applicant): Developmental disorders of the nervous system are amongst the most catastrophic illnesses, and those effecting the assembly and function of the cerebral cortex, including epilepsy, schizophrenia, and autism are particularly devastating and often refractory to treatment. A common feature uniting these disparate neurologic and psychiatric disorders is the malfunction of inhibitory cortical circuitry and a shared neurodevelopmental etiology. One significant source of pathological vulnerability occurs during embryonic development, when cortical interneurons migrate from their place of origin in the ventral forebrain to the overlying cerebral cortex. Migratory cortical interneurons sense and respond to numerous guidance cues in order to make correct navigational decisions as they exit the ventral forebrain, enter the cerebral cortex, travel in streams of migratory interneurons, and finally infiltrate the cortical plate and target discrete cortical laminae. Molecular mechanisms allowing cortical interneurons to make correct decisions along their migratory paths are ill defined. Our recently published and ongoing work indicate novel and surprising roles for the ubiquitous c-Jun-N- terminal kinase (JNK) signaling pathway in orchestrating key navigational decisions made by migrating cortical interneurons, including those enabling their entrance into the cerebral cortex, selection of migratory streams, and correct timing of migratory stream departure. These observations lead to our central hypothesis that precise spatial and temporal control of JNK activity enables appropriate construction of cortical circuitry by facilitating the guided migration of cortical interneurons. The objective of our proposal is to elucidate cellular and molecular mechanisms eliciting dynamic changes in cellular behavior that are essential for orienting neuronal migration in response to extracellular guidance cues. We propose to: 1) Determine how JNK activity regulates nucleokinesis, branching, and subcellular localization of the microtubule regulatory protein doublecortin (Dcx) during cortical interneuron migration, 2) Evaluate the functional significance of JNK-Dcx interactions during guided migration and differentiation of cortical interneurons, and 3) Determine how intracellular JNK activity controls timing of migratory stream exit and intracortical dispersion. We combine mouse genetics with powerful imaging techniques and novel molecular tools to investigate the cellular and molecular biology of cortical interneuron migration in situ. Our results will provide critical insight into fundamental mechanisms mediating guided neuronal migration in the developing cerebral cortex, which is imperative for understanding and eventually treating severe disorders of cortical connectivity.

描述（由申请人提供）：神经系统的发育障碍是最严重的疾病之一，影响大脑皮层的组装和功能的疾病，包括癫痫、精神分裂症和自闭症，是特别有害的，并且通常难以治疗。这些不同的神经和精神疾病的共同特征是抑制性皮层回路的功能障碍和共同的神经发育病因学，病理脆弱性的一个重要来源发生在胚胎发育过程中。皮质中间神经元从腹侧前脑的起源地迁移到覆盖的大脑皮层。迁移性皮质中间神经元感知并响应大量的引导线索，以便在离开腹侧前脑、进入大脑皮层、成流行进时做出正确的导航决策。迁移的中间神经元，最终渗透到皮质板并瞄准离散的皮质层，允许皮质中间神经元沿着其迁移路径做出正确决定的分子机制是有问题的。我们最近发表和正在进行的工作表明，普遍存在的 c-Jun-N- 末端激酶 (JNK) 信号通路在协调迁移皮质中间神经元做出的关键导航决策中发挥着新颖且令人惊讶的作用，包括那些使其能够进入大脑皮层的决策。这些观察结果得出了我们的中心假设：JNK 活动的精确空间和时间控制通过促进皮层中间神经元的引导迁移来实现皮层回路的适当构建。我们建议的目标是阐明引起细胞行为动态变化的细胞和分子机制，这对于响应细胞外指导线索定向神经元迁移至关重要。我们建议：1）确定 JNK 活性如何调节核分裂、分支和亚细胞定位。皮层中间神经元迁移过程中微管调节蛋白双皮质素 (Dcx) 的作用，2) 评估 JNK-Dcx 相互作用在引导迁移和分化过程中的功能意义3) 确定细胞内 JNK 活性如何控制迁移流退出和皮质内分散的时间。我们将小鼠遗传学与强大的成像技术和新颖的分子工具相结合，以研究皮质中间神经元原位迁移的细胞和分子生物学。对介导发育中的大脑皮层中引导神经迁移的基本机制提供了重要的见解，这对于理解和最终治疗严重的皮质连接障碍至关重要。