Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
Division of Neuroscience, IRCCS, San Raffaele Hospital, Milan, Italy.
Elife. 2023 Feb 13;12:e77441. doi: 10.7554/eLife.77441.
In the developing central nervous system, oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes, which form myelin around axons. Oligodendrocytes and myelin are essential for the function of the central nervous system, as evidenced by the severe neurological symptoms that arise in demyelinating diseases such as multiple sclerosis and leukodystrophy. Although many cell-intrinsic mechanisms that regulate oligodendrocyte development and myelination have been reported, it remains unclear whether interactions among oligodendrocyte-lineage cells (OPCs and oligodendrocytes) affect oligodendrocyte development and myelination. Here, we show that blocking vesicle-associated membrane protein (VAMP) 1/2/3-dependent exocytosis from oligodendrocyte-lineage cells impairs oligodendrocyte development, myelination, and motor behavior in mice. Adding oligodendrocyte-lineage cell-secreted molecules to secretion-deficient OPC cultures partially restores the morphological maturation of oligodendrocytes. Moreover, we identified L-type prostaglandin D synthase as an oligodendrocyte-lineage cell-secreted protein that promotes oligodendrocyte development and myelination in vivo. These findings reveal a novel autocrine/paracrine loop model for the regulation of oligodendrocyte and myelin development.
在中枢神经系统发育过程中，少突胶质前体细胞 (OPC) 分化为少突胶质细胞，后者在轴突周围形成髓鞘。少突胶质细胞和髓鞘对中枢神经系统的功能至关重要，这一点在脱髓鞘疾病（如多发性硬化症和白质营养不良症）中表现得尤为明显，因为这些疾病会导致严重的神经系统症状。尽管已经报道了许多调节少突胶质细胞发育和髓鞘形成的细胞内机制，但仍不清楚少突胶质细胞谱系细胞（OPC 和少突胶质细胞）之间的相互作用是否会影响少突胶质细胞的发育和髓鞘形成。在这里，我们发现阻断少突胶质细胞谱系细胞中囊泡相关膜蛋白 (VAMP) 1/2/3 依赖性胞吐作用会损害小鼠的少突胶质细胞发育、髓鞘形成和运动行为。向分泌缺陷的 OPC 培养物中添加少突胶质细胞谱系细胞分泌的分子部分恢复了少突胶质细胞的形态成熟。此外，我们还鉴定出 L 型前列腺素 D 合酶作为一种少突胶质细胞谱系细胞分泌的蛋白，它可以促进体内少突胶质细胞的发育和髓鞘形成。这些发现揭示了一个调节少突胶质细胞和髓鞘发育的新的自分泌/旁分泌循环模型。
