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

 描述（由申请人提供）：神经系统发育障碍是最严重的疾病之一，影响大脑皮层组装和功能的疾病，包括癫痫、精神分裂症和自闭症，特别具有破坏性，通常难以治疗。一个共同的特点，这些不同的神经和精神疾病是功能障碍的抑制皮层电路和共同的神经发育病因。病理脆弱性的一个重要来源发生在胚胎发育期间，当皮层中间神经元从其腹侧前脑中的起源地迁移到上覆的大脑皮层时。迁移的皮层中间神经元感知并响应于许多引导线索，以便在它们离开腹侧前脑、进入大脑皮层、在迁移的中间神经元流中行进、并且最终渗透皮层板并靶向离散的皮层层时做出正确的导航决策。允许皮层中间神经元沿着它们的迁移路径做出正确决定的分子机制是不明确的。我们最近发表和正在进行的工作表明，无处不在的c-Jun-N-末端激酶（JNK）信号通路在协调迁移皮层中间神经元所做的关键导航决策中发挥了新颖和令人惊讶的作用，包括使其能够进入大脑皮层，选择迁移流和正确的迁移流离开时间。这些观察结果导致我们的中心假设，精确的空间和时间控制JNK活性，使适当的建设皮层电路，促进引导迁移皮层中间神经元。我们的建议的目的是阐明细胞和分子机制引起细胞行为的动态变化，是必不可少的定向神经元迁移响应细胞外的指导线索。我们建议：1）确定JNK活性如何调节皮层中间神经元迁移过程中微管调节蛋白双皮质素（Dcx）的核分裂、分支和亚细胞定位，2）评估JNK-Dcx相互作用在皮层中间神经元引导迁移和分化过程中的功能意义，和3）确定细胞内JNK活性如何控制迁移流退出和皮层内分散的时间。我们将联合收割机小鼠遗传学与强大的成像技术和新的分子工具相结合，研究皮质中间神经元原位迁移的细胞和分子生物学。我们的研究结果将提供关键的洞察力的基本机制介导的引导神经元迁移在发育中的大脑皮层，这是必不可少的理解和最终治疗严重的皮质连接障碍。

 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.