Cellular and Molecular Mechanisms Underlying Neuronal Type-specific Axon Regeneration

项目说明 神经系统损伤后轴突再生失败是 功能恢复。轴突再生受内在和外在线索的控制 来自神经元和周围的神经胶质环境。然而，我们对此的理解 神经胶质细胞对轴突再生的控制仍然不完整。在这里，我们研究轴突 果蝇幼虫体内明确感觉神经元的再生。这个活体模型 提供了一个用单细胞分辨率研究轴突再生的强大机会 和遗传上的可驯性。我们的试点研究通过发现一个关键的 神经胶质细胞-神经元相互作用，以神经胶质传递的形式，参与指定 神经元类型的轴突再生差异。基于这些发现，我们假设 这种神经胶质传递协调神经元类型特定轴突的再生。具体来说， 我们认为，轴突切断激活了胶质细胞中的钙信号，从而引发了神经胶质细胞的传递。 导致细胞外ATP的积累。然后，ATP被ECTO-5‘- 在激活所选神经元中的腺苷受体之前，将核苷酸酶转化为腺苷 类型，导致神经元类型特异性钙信号和轴突再生。在这个项目中， 我们将利用果蝇遗传学的力量，将其与多学科相结合 检验这一假说的方法。因为轴突再生机制是 保守地说，我们的发现可能会与包括哺乳动物在内的其他物种相关。

Project description Failure in axon regeneration after nervous system lesion is a major roadblock for functional recovery. Axon regeneration is controlled by both intrinsic and extrinsic cues from both neurons and surrounding glial environment. However, our understanding of glial control of axon regeneration remains incomplete. Here, we investigate axon regeneration of well-defined sensory neurons in Drosophila larvae. This in vivo model offers a powerful opportunity to investigate axon regeneration with single-cell resolution and genetic tractability. Our pilot study has made novel findings by discovering a critical involvement of glia-neuron interactions, in the form of gliotransmission, in specifying axon regenerative differences of neuron types. Based on these findings, we hypothesize that gliotransmission orchestrates neuron type-specific axon regeneration. Specifically, we propose that axotomy activates Ca2+ signals in glial cells to elicit gliotransmission, leading to accumulation of extracellular ATP. ATP is then converted by ecto-5’- nucleotidases to adenosine before activating adenosine receptors in the select neuron type, resulting in neuron type-specific Ca2+ signals and axon regeneration. In this project, we will leverage the power of Drosophila genetics and combine it with multidisciplinary approaches to test this hypothesis. Because axon regeneration mechanisms are conserved, our findings will likely be relevant to other species including mammals.