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

 描述(申请人提供)：神经系统发育障碍是最灾难性的疾病之一，而那些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，尤其具有破坏性，而且往往难以治疗。这些不同的神经学和精神病学疾病的一个共同特征是抑制性皮质回路的故障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，当皮质中间神经元从它们在腹侧前脑的起始处迁移到覆盖的大脑皮层时。在离开腹侧前脑，进入大脑皮层，在一连串的迁移中间神经元流中移动，最后渗透到皮质板和目标皮质板时，迁移的皮质间神经元感知和响应大量的指导信号，以便做出正确的导航决定。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尚不清楚。我们最近发表的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的皮质间神经元做出的关键导航决策中扮演着新的和令人惊讶的角色，包括那些使它们能够进入大脑皮层的决策，迁移流的选择，以及正确的迁移流离开的时间。这些观察结果导致了我们的中心假设，即对JNK活性的精确时空控制可以通过促进皮质中间神经元的引导迁移来适当地构建皮质回路。我们建议的目的是阐明引起细胞行为动态变化的细胞和分子机制，这些机制对于定位神经元在细胞外引导线索下的迁移至关重要。我们建议：1)确定JNK活性如何在皮质神经元间迁移过程中调节微管调节蛋白Doublecortin(DCX)的核运动、分支和亚细胞定位；2)评估JNK-DCX相互作用在引导皮质间神经元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的分子工具相结合，研究皮层神经元间原位迁移的细胞和分子生物学。我们的结果将为在发育中的大脑皮层调节引导神经元迁移的基本机制提供关键的见解，这对于理解和最终治疗严重的皮质连接障碍是必不可少的。

 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.