Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China.
Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.
J Neurosci. 2023 Jan 11;43(2):211-220. doi: 10.1523/JNEUROSCI.1087-22.2022. Epub 2022 Dec 5.
In the developing cortex, excitatory neurons migrate along the radial fibers to their final destinations and build up synaptic connection with each other to form functional circuitry. The shaping of neuronal morphologies by actin cytoskeleton dynamics is crucial for neuronal migration. However, it is largely unknown how the distribution and assembly of the F-actin cytoskeleton are coordinated. In the present study, we found that an actin regulatory protein, coronin 2B, is indispensable for the transition from a multipolar to bipolar morphology during neuronal migration in ICR mice of either sex. Loss of coronin 2B led to heterotopic accumulation of migrating neurons in the intermediate zone along with reduced dendritic complexity and aberrant neuronal activity in the cortical plate. This was accompanied by increased seizure susceptibility, suggesting the malfunction of cortical development in coronin 2B-deficient brains. Coronin 2B knockdown disrupted the distribution of the F-actin cytoskeleton at the leading processes, while the migration defect in coronin 2B-deficient neurons was partially rescued by overexpression of Rac1 and its downstream actin-severing protein, cofilin. Our results collectively reveal the physiological function of coronin 2B during neuronal migration whereby it maintains the proper distribution of activated Rac1 and the F-actin cytoskeleton. Deficits in neuronal migration during cortical development result in various neurodevelopmental disorders (e.g., focal cortical dysplasia, periventricular heterotopia, epilepsy, etc.). Most signaling pathways that control neuronal migration process converge to regulate actin cytoskeleton dynamics. Therefore, it is important to understand how actin dynamics is coordinated in the critical processes of neuronal migration. Herein, we report that coronin 2B is a key protein that regulates neuronal migration through its ability to control the distribution of the actin cytoskeleton and its regulatory signaling protein Rac1 during the multipolar-bipolar transition in the intermediate zone, providing insights into the molecular machinery that drives the migration process of newborn neurons.
在发育中的皮质中，兴奋性神经元沿着放射状纤维迁移到它们的最终目的地，并与彼此建立突触连接，形成功能性回路。肌动蛋白细胞骨架动力学对神经元迁移过程中神经元形态的形成至关重要。然而，actin 细胞骨架的分布和组装是如何协调的，在很大程度上还不清楚。在本研究中，我们发现，actin 调节蛋白 coronin 2B 在 ICR 雌雄小鼠的神经元迁移过程中，从多极到双极形态的转变中是必不可少的。coronin 2B 的缺失导致迁移神经元在中间带的异位积累，同时伴随着树突复杂性降低和皮质板中神经元活动异常。这伴随着癫痫易感性的增加，表明 coronin 2B 缺陷大脑的皮质发育功能障碍。coronin 2B 的敲低扰乱了突起前端的 F-actin 细胞骨架的分布，而 coronin 2B 缺陷神经元的迁移缺陷部分被 Rac1 及其下游的 actin 切割蛋白 cofilin 的过表达所挽救。我们的研究结果共同揭示了 coronin 2B 在神经元迁移过程中的生理功能，它维持了激活的 Rac1 和 F-actin 细胞骨架的正确分布。皮质发育过程中神经元迁移的缺陷导致各种神经发育障碍（例如，局灶性皮质发育不良、脑室周围异位症、癫痫等）。控制神经元迁移过程的大多数信号通路都集中在调节 actin 细胞骨架动力学上。因此，了解 actin 动力学如何在神经元迁移的关键过程中协调是很重要的。在这里，我们报告 coronin 2B 是一种关键蛋白，通过控制 actin 细胞骨架的分布及其在中间带的多极-双极转变中的调节信号蛋白 Rac1，调节神经元迁移，为驱动新生神经元迁移过程的分子机制提供了新的见解。
