Molecular and cell biological mechanisms mediating re-establishment and maintenance of cell polarity in the developing CNS

介导发育中中枢神经系统细胞极性重建和维持的分子和细胞生物学机制

• 批准号: MR/N008588/1
• 负责人: Raman Das
• 金额: $ 149.4万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN008588%2F1
• 关键词: Molecular; cell; biological; mechanisms; mediating

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 key proteins that allow them to distinguish their front from their back, causing them to lose polarity. Following this, the neuron must now rapidly repolarise itself. This repolarisation is crucial, as it allows the neuron to extend a long cell-process, called an axon, which makes connections with its targets, which could be muscles or other neurons. In the developing embryo, the neuron repolarises in response to external signals from the surrounding tissue. These external cues determine the position of this repolarisation 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. I propose to study the molecular and cellular mechanisms that direct this key cell-biological process, and a better understanding of this will ultimately lead to the possibility of manipulating and/or stimulating it to treat neural disorders during embryogenesis and adulthood. Additionally, many cancer cells also undergo a very similar repolarisation process during the process of metastasis, which allows them to migrate to different locations and form more tumours. It is likely that the cancer cells do this in a way similar to newborn neurons, so understanding neuron repolarisation will potentially also help us to understand how cancer cells migrate to form secondary tumours. Thus understanding how cells repolarise in response to surrounding tissues has far-reaching consequences.

发育中胚胎脊髓中的新生神经元会脱落尖端以移动到最终位置。由于这种脱落事件，这些新生神经元失去了使它们能够区分正面和背面的关键蛋白质，导致它们失去极性。此后，神经元必须快速重新极化。这种复极化至关重要，因为它允许神经元延伸一个称为轴突的长细胞过程，轴突与其目标（可能是肌肉或其他神经元）建立连接。在发育中的胚胎中，神经元响应来自周围组织的外部信号而重新极化。这些外部线索决定了这种复极化的位置，从而决定了轴突行进的方向，或者轴突是否形成。因此，这是一个对于功能性神经元回路的形成至关重要的关键事件。我建议研究指导这一关键细胞生物学过程的分子和细胞机制，更好地理解这一过程将最终导致操纵和/或刺激它来治疗胚胎发生和成年期间神经疾病的可能性。此外，许多癌细胞在转移过程中也会经历非常相似的复极化过程，这使得它们能够迁移到不同的位置并形成更多的肿瘤。癌细胞的这种方式很可能与新生神经元类似，因此了解神经元复极化也可能有助于我们了解癌细胞如何迁移形成继发性肿瘤。因此，了解细胞如何响应周围组织而重新极化具有深远的影响。