Signaling mechanism for synapse formation and function regulated by the release of GPI-anchored synaptogenic factors from astrocytes

神经元和神经胶质细胞之间的动态相互作用对于建立正确的结构和功能至关重要 神经系统。特别是，星形胶质细胞是突触发育的多个步骤的强大调节者 和功能。然而，我们缺乏对信号分子是如何从 星形胶质细胞到神经元，以调节突触的形成。在这项提案中，我们提出了GDE3、 星形胶质细胞表面糖基磷脂酰肌醇(GPI)锚定蛋白的主要调节因子是 是突触发育和功能所必需的。GDE3促进GPI锚定蛋白从 星形胶质细胞有两种释放方式：GPI释放和胞外囊泡释放。在本提案中，我们将定义 GDE3活性形式的突触生成因子及其下游效应因子的释放机制。重要的是 我们将确定GPI-Anclage在突触发育中的具体作用和在发育中的功能 大脑。我们的结果将揭示星形胶质细胞-神经元通讯的一种新的信号机制，并有助于 突触源性缺陷所致疾病的替代治疗干预设计。

Dynamic interplay between neurons and glia is critical to establish the proper structure and function of the nervous system. In particular, astrocytes are powerful regulators of the multiple steps of synapse development and function. However, we lack mechanistic understanding of how signaling molecules are delivered from astrocytes to neurons to regulate the synaptogenesis. In this proposal, we present evidence that GDE3, the major regulator of the glycosylphosphatidylinositol (GPI)-anchored proteins on the astrocyte surface, is required for synapse development and function. GDE3 facilitates the release of GPI-anchored proteins from astrocytes in two modes: GPI-shedding and extracellular vesicular release. In this proposal, we will define the release mechanism of the active form of synaptogenic factors and downstream effectors of GDE3. Importantly, we will determine the specific role of GPI-anchorage in synapse development and function in the developing brain. Our results will reveal a novel signaling mechanism of astrocyte-neuron communications and aid the design of alternative therapeutic interventions for diseases caused by synaptogenic defects.