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

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质内连接，而深层神经元的轴突形成脑下连接。除了轴突束的形成使得不同脑区域之间能够进行通信之外，大脑皮层的执行作用还需要高度极化的神经元上的动作电位的单向流动。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质功能至关重要。我们最近发现肌醇需要酶1（Ire 1 α）对于获得上层神经元命运和建立极化神经元形态是必需的。此外，我们有初步的数据，Ire 1 α作为一个典型的调节蛋白质翻译在发育中的神经元。我们提出了一个实验计划，以揭示Ire 1 α介导的神经元命运和极性建立的分子机制。它包括分析细胞骨架稳定性，深入研究背前脑特异性Ire 1 α KO小鼠的神经发生，质谱和深度RNA测序方法来描述皮质生成过程中Ire 1 α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研究Ire1α丢失对皮质连接的终点后果。此外，我们计划研究翻译速率调节的全球机制及其参与神经元细胞命运和神经元极化的建立。我们的研究将大大有助于理解在大脑发育过程中发挥作用的信号级联反应，也有助于扩大Ire 1 α参与生物过程的范围，以前主要与细胞应激和病理学有关，其中包括神经变性。

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.