Dynamic modulation of membrane tension and mechanosensitive ion channel activity steers the nerve growth cone

膜张力和机械敏感离子通道活性的动态调节引导神经生长锥

• 批准号: 436091-2013
• 负责人: SharifNaeini, Reza
• 金额: $ 2.33万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=574273
• 关键词: Dynamic; modulation; membrane; tension; mechanosensitive

The precise wiring of the developing nervous system depends on the path-finding abilities of the neuronal growth cone (GC), a highly dynamic sensory structure at the tip of growing axons. Growth cone turning is a fundamental behavior during axon guidance, yet its underlying mechanisms are incompletely understood. The GC membrane contains mechanosensitive ion channels (MSC) that are proposed to sense changes in membrane tension and transduce these changes into electrical signals. The objective of this program is to understand how the GC cytoskeleton, membrane tension, and the activity of mechanosensitive ion channels interact together to steer the growth cone. We hypothesize that in response to a gradient of guidance cues, GC turning is induced by an asymmetrical rigidification of the cytoskeleton, which alters the distribution of tension forces across the GC membrane and leads to an asymmetry in MSC activity. We will use a combination of molecular and cellular biology, live fluorescence imaging and pharmacology to examine the spatio-temporal distribution of the cytoskeleton and MSC activity across the GC membrane during its turning. These experiments will shed light onto a novel aspect of growth cone guidance. This combination of experimental approaches is unique and novel. It will enable us to further our understanding of GC steering. Elucidating how MSCs and membrane tension are involved in guided axonal growth will provide important insights into the intricate signaling mechanisms underlying neuronal wiring, which is fundamental for normal brain development and functional recovery after injury and diseases.

发育中的神经系统的精确布线取决于神经元生长锥（GC）的寻路能力，神经元生长锥是生长轴突尖端的高度动态感觉结构。生长锥转向是轴突导向过程中的一个基本行为，但其内在机制尚未完全了解。GC膜含有机械敏感离子通道（MSC），其被提出用于感测膜张力的变化并将这些变化转化为电信号。这个项目的目的是了解GC细胞骨架，膜张力和机械敏感离子通道的活性如何相互作用以控制生长锥。 我们假设，在响应梯度的指导线索，GC转向诱导的细胞骨架的不对称硬化，这改变了整个GC膜的张力分布，并导致MSC活动的不对称性。我们将使用分子和细胞生物学，活体荧光成像和药理学的组合来研究细胞骨架的时空分布和MSC在GC膜上的活动。 这些实验将揭示生长锥引导的一个新方面。这种实验方法的结合是独特和新颖的。它将使我们能够进一步了解GC引导。阐明MSC和膜张力如何参与引导轴突生长将为神经元布线背后复杂的信号机制提供重要见解，这对于正常的大脑发育和损伤和疾病后的功能恢复至关重要。