The role of cellular stress-associated protein Ire1α in the development of the cerebral cortex.

细胞应激相关蛋白 Ire1α 在大脑皮层发育中的作用。

• 批准号: 455114826
• 负责人: Professor Dr. Victor Tarabykin
• 金额: --
• 依托单位: Institut für Zell- und Neurobiologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/455114826?language=en
• 关键词: role; cellular; stress; associated; protein

Formation of cortical architecture during development is fundamental for mature brain connectivity. Neurons of upper layers preferentially establish intracortical connections, whereas the axons of deeper layer neurons form subcerebral connections. Besides formation of axonal tracts enabling communication between different brain regions, the executive role of the cerebral cortex requires a unidirectional flow of action potentials on highly polarized neurons. Acquisition of neuronal cell fate and axon-dendrite polarity during development is therefore crucial for uninterrupted cortical functions. We have recently discovered that Inositol-Requiring Enzyme 1, Ire1α, is necessary for acquisition of upper layer neuronal fate and establishment of polarized neuronal morphology. Moreover, we have preliminary data that Ire1α acts as a canonical regulator of protein translation in developing neurons. We propose an experimental plan to reveal the molecular mechanisms of Ire1α-mediated neuronal fate and polarity establishment. It includes the analysis of the cytoskeleton stability, thorough investigation of neurogenesis in dorsal forebrain-specific Ire1α KO mice, mass-spectrometry and deep RNA-sequencing approaches to delineate Ire1α-dependent cellular signaling during corticogenesis. We also propose to investigate the end-point consequences of Ire1α loss for cortical connectivity using a cutting-edge whole brain imaging technique. Further, we plan to investigate the global mechanisms of translational rate regulation and its involvement in establishment of neuronal cell fate and polarization of neurons. Our research will significantly contribute to the understanding of signaling cascades at play during brain development, but also to broadening the scope of Ire1α involvement in biological processes, previously majorly linked to cellular stress and pathologies, among others neurodegeneration.

发育过程中皮层结构的形成是成熟大脑连接的基础。上层神经元优先建立皮层内连接，而较深层神经元的轴突则形成脑下连接。除了形成轴突束使大脑不同区域之间的通信，大脑皮层的执行作用需要在高极化神经元上单向流动的动作电位。因此，在发育过程中获得神经元细胞命运和轴突-树突极性对于不间断的皮层功能至关重要。我们最近发现肌醇要求酶1 （Ire1α）对于上层神经元命运的获得和极化神经元形态的建立是必需的。此外，我们有初步的数据表明，Ire1α在发育中的神经元中作为蛋白质翻译的典型调节因子。我们提出了一个实验计划来揭示ire1 α-介导的神经元命运和极性建立的分子机制。它包括细胞骨架稳定性分析，对背前脑特异性Ire1α KO小鼠神经发生的深入研究，质谱法和深度rna测序方法来描述皮质发生过程中Ire1α依赖性细胞信号传导。我们还建议使用尖端的全脑成像技术来研究Ire1α缺失对皮质连通性的终点后果。进一步，我们计划研究翻译速率调控的全球机制及其在神经元细胞命运和神经元极化的建立中的作用。我们的研究将大大有助于理解大脑发育过程中的信号级联反应，同时也拓宽了Ire1α参与生物过程的范围，这些生物过程以前主要与细胞应激和病理等神经变性有关。