Cell-biological mechanisms directing primary cilium mediated control of neuron polarisation

指导初级纤毛介导的神经元极化控制的细胞生物学机制

• 批准号: MR/X008363/1
• 负责人: Raman Das
• 金额: $ 73.31万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX008363%2F1
• 关键词: Cell; biological; mechanisms; directing; primary

A key feature of neurons is their ability to respond to cues from the surrounding tissues which allow them to distinguish their front from their back and thus achieve polarisation. Newborn neurons in the spinal cord of the developing embryo shed their tips to move to their final location. As a result of this shedding event, these newborn neurons lose the key proteins that define their polarity as well as their cellular antenna, called the primary cilium, which allows these cells to sense external cues from the surrounding tissues. Consequently, newborn neurons stop responding to Shh signalling and exit the cell cycle, which is a key step of neuronal differentiation. Following this, the neuron must now rapidly re-establish its polarity. This step is crucial, as it allows the neuron to extend a long cell-process, called an axon, which makes connections with its targets, such as muscles or other neurons. In the developing embryo, the neuron polarises in response to external cues from the surrounding tissue. These external cues determine the orientation of this polarisation and therefore determine the direction in which the axon will travel, or if it forms at all. This is thus a critical event that is essential for the formation of functional neuronal circuitry. We have recently discovered that newborn neurons quickly reassemble a new primary cilium as they prepare to extend an axon. This new primary cilium now allows the newborn neuron to switch its response to Shh signalling, which now acts to determine the direction in which the axon projects. This proposal aims to investigate the cell biological mechanisms that direct this switch in the interpretation of Shh signalling by the reassembled primary cilium. Furthermore, we also aim to investigate how signalling through the reassembled primary cilium directs remodelling of the neuronal cytoskeleton to generate the characteristic neuronal morphology. To achieve this, we will use cutting-edge microscopy techniques to make movies of polarising neurons in developing embryos and combine these with super-resolution fluorescence imaging of fixed embryonic tissue. This will allow us to identify and modulate the mechanisms that mediate the switch in the cellular response to Shh signalling and how this influences cytoskeletal remodelling in differentiating neurons. This work may lead to the development of novel clinical interventions to promote this process in the case of neurodevelopmental disorders or following injury during adulthood.

神经元的关键特征是它们能够从周围组织中响应线索，从而使他们能够将其前部与背部区分开，从而实现极化。发育中的胚胎的脊髓中的新生神经元脱落了他们的最终位置的技巧。由于这一脱落事件，这些新生神经元失去了定义其极性以及其细胞天线的关键蛋白，称为主要的纤毛，这使这些细胞可以从周围组织中感知外部线索。因此，新生儿神经元停止反应SHH信号并退出细胞周期，这是神经元分化的关键步骤。此后，神经元现在必须迅速重新建立其极性。此步骤至关重要，因为它允许神经元扩展一个称为轴突的长细胞过程，该过程与靶标（例如肌肉或其他神经元）建立连接。在发育中的胚胎中，神经元偏振响应周围组织的外部线索。这些外部提示决定了这种极化的方向，因此确定了轴突的传播方向，或者根本不形成。因此，这是一个关键事件，对于形成功能性神经元电路至关重要。我们最近发现，新生儿神经元在准备延伸轴突时迅速重新组装新的原发性纤毛。现在，这种新的原发性纤毛使新生神经元可以切换其对SHH信号的反应，现在，该神经元可以确定轴突投射的方向。该建议旨在研究将这种转换指导通过重新组装的原代纤毛解释SHH信号传导的细胞生物学机制。此外，我们还旨在调查通过重新组装的原代纤毛发出信号如何指导神经元细胞骨架的重塑以产生特征性的神经元形态。为了实现这一目标，我们将使用尖端的显微镜技术在开发胚胎中制作偏振神经元的电影，并将它们与固定胚胎组织的超分辨率荧光成像相结合。这将使我们能够识别和调节介导细胞响应中SHH信号转导的开关的机制，以及这如何影响分化神经元中细胞骨架重塑。这项工作可能会导致新的临床干预措施的发展，以在神经发育障碍或成年期间受伤后促进这一过程。