Function of Thy-1 (CD90) in the neuron – astrocyte communication

Thy-1 （CD90）是一种表达于活化的微血管内皮细胞、成纤维细胞、间充质干细胞（MSC）和成熟神经元的细胞表面分子。在此之前，我们发现Thy-1是微血管内皮细胞上的一种激活依赖性细胞粘附分子。在成纤维细胞中，我们证明了Thy-1控制增殖和凋亡之间的平衡以及成纤维细胞向肌成纤维细胞的分化。最后，我们发现Thy-1是间充质干细胞上的一个调节分子，可以促进骨形成，从而抑制脂肪形成和肥胖。虽然Thy-1启动子作为一种神经元特异性启动子被广泛应用于投射神经元的转基因表达，但其在神经元上高度表达的内源性Thy-1蛋白的功能至今仍是一个谜。神经元整合在星形胶质细胞、小胶质细胞和少突胶质细胞的复杂网络中。星形胶质细胞和神经元的通讯调节细胞外环境的稳态、脑代谢、脑微循环和血脑屏障。在受伤期间，星形胶质细胞从正常的功能“静止”状态被激活，并改变其许多特性，这一过程被称为星形胶质细胞形成。星形胶质细胞形成的基本功能包括保护神经细胞、抑制炎症和感染、保存组织和功能。相反，持续的反应性星形胶质细胞增生可能是有害的，因为轴突再生受到抑制。Thy-1在神经元上高度表达，在星形胶质细胞上表达多种潜在受体，并与星形胶质细胞表面结合。重要的是，星形胶质细胞在没有神经变性的情况下，当神经元上缺乏Thy-1时，会表达激活的迹象。因此，我们假设Thy-1参与了神经元到星形胶质细胞的信号传递，而这种信号传导使星形胶质细胞处于静止状态。因此，在本项目中，我们旨在阐明Thy-1在生理和病理生理条件下神经元-星形胶质细胞通讯中的作用。通过与野生型小鼠相比，分析Thy-1神经元特异性缺失小鼠的星形胶质细胞，我们将研究神经元Thy-1对维持星形胶质细胞静止状态以及星形胶质细胞激活、增殖和凋亡的影响。此外，我们将确定Thy-1介导星形胶质细胞活化的调控机制，并研究神经元Thy-1表达的调控。最后，我们将研究神经元Thy-1对复杂神经网络中其他脑细胞如少突胶质细胞和小胶质细胞的影响。我们的发现将大大有助于理解星形胶质细胞和神经元之间的交流和相互作用，并可能为神经系统疾病的治疗提供新的靶点。

Thy-1 (CD90) is a cell surface molecule expressed on activated microvascular endothelial cells, fibroblasts, mesenchymal stem cells (MSC), and mature neurons. Previously, we identified Thy-1 as an activation-dependent cell adhesion molecule on microvascular endothelial cells. In fibroblasts, we demonstrated that Thy-1 controls the balance between proliferation and apoptosis as well as the differentiation of fibroblasts to myofibroblasts. Finally, we identified Thy-1 as a regulator molecule on MSC that promotes osteogenesis and thus bone formation while inhibiting adipogenesis and obesity. While the Thy-1 promoter is well known and widely used as a neuron-specific promoter for transgenic expression in projections neurons, the function of the endogenous Thy-1 protein highly expressed on neurons has remained enigmatic so far. Neurons are integrated in a complex network of astrocytes, microglia and oligodendrocytes. Communication of astrocytes and neurons regulates homeostasis of the extracellular milieu, brain metabolism, cerebral microcirculation and the blood brain barrier. During injury, astrocytes get activated from a normal functional, “quiescent” state and change many of their properties, a process called astrogliosis. Essential functions of astrogliosis include the protection of neural cells, the restriction of inflammation and infection, and the preservation of tissue and function. In contrast, persistent reactive astrogliosis can be harmful due to inhibition of axonal regeneration.Thy-1 is highly expressed on neurons, several potential receptors are expressed on astrocytes and Thy-1 binds to the astrocytic surface. Importantly, astrocytes express signs of activation when Thy-1 is lacking on neurons in the absence of neurodegeneration. Therefore, we hypothesize that Thy-1 contributes to signaling from neurons to astrocytes and that this signaling keeps astrocytes in a quiescent state.In the present project, we therefore aim at elucidating the role of Thy-1 in neuron-astrocyte communication under physiological and pathophysiological conditions. By analysis of astrocytes in mice with a neuron-specific deletion of Thy-1 compared to wildtype mice we will study the impact of neuronal Thy-1 for the maintenance of a quiescence state in astrocytes as well as for astrocyte activation, proliferation and apoptosis. Furthermore, we will identify the mechanism of Thy-1-mediated control of astrocyte activation, and investigate the regulation of neuronal Thy-1 expression. Finally, the impact of neuronal Thy-1 on other brain cells within the complex neural network like oligodendrocytes and microglial cells will be investigated.Our findings will substantially contribute to the understanding of the communication and interaction between astrocytes and neurons and might possibly provide new targets for the treatment of neurological diseases.