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

发育中的神经系统的精确连接依赖于神经元生长锥(GC)的寻路能力，GC是生长轴突顶端的一种高度动态的感觉结构。生长锥体旋转是轴突引导过程中的一种基本行为，但其潜在的机制尚不完全清楚。GC膜含有机械敏感离子通道(MSC)，被认为可以感知膜张力的变化，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来控制生长锥。**我们假设，在对引导信号的梯度做出反应时，GC转向是由细胞骨架的不对称强化所诱导的，这改变了GC膜上的张力分布，并导致MSC活性的不对称。我们将结合分子和细胞生物学、实时荧光成像和药理学来研究GC膜翻转过程中细胞骨架和MSC活性的时空分布。**这些实验将揭示生长锥体引导的一个新方面。这种实验方法的结合是独特和新颖的。这将使我们能够加深对GC转向的理解。阐明MSCs和膜张力是如何参与引导轴突生长的，将为了解神经元连接的复杂信号机制提供重要的见解，而神经元连接是脑正常发育和损伤和疾病后功能恢复的基础。

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.**