The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction. These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury. During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses. In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased. Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation. Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan.

中文翻译：

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活化素受体调节健康和疾病中的少突胶质细胞谱系。

髓磷脂最普遍的神经系统疾病包括围产期脑损伤，导致婴儿脑瘫和成人多发性硬化。尽管这些疾病具有不同的病因，但它们共有共同的神经病理学特征，即祖细胞分化为产生髓磷脂的少突胶质细胞失败和缺乏髓磷脂，这是临床上尚未满足的需求。在这里，我们揭示了两种疾病共有的分子病理学是激活素受体的失调，并且在发育中和损伤后大多数髓磷脂生成都需要激活素受体信号转导。利用少突胶质细胞系细胞中所有激活素受体信号转导的条件性条件敲除，我们发现该信号是通过调节少突胶质细胞分化和髓鞘紧缩而进行髓鞘形成所必需的。发现这些过程依赖于活化素受体亚型Acvr2a，其在少突胶质细胞分化和发育中以及髓鞘损伤后的轴突鞘化过程中表达。在有效的髓磷脂再生过程中，Acvr2a的上调与Acvr2b的下调相吻合，Acvr2b是一种具有相对较高配体亲和力的受体亚型。已显示Acvr2b对于激活素受体驱动的少突胶质细胞分化是可有可无的，并且其过表达足以削弱上述配体驱动的应答。在人围产期脑损伤和多发性硬化组织的活跃髓鞘或再髓鞘区域中，表达Acvr2a的少突胶质细胞谱系细胞多于表达Acvr2b的细胞，而在非修复性病变中，Acvr2b +细胞增加。因此，我们建议在人类白质损伤后，Acvr2b表达的增加会隔离配体，从而损害Acvr2a驱动的少突胶质细胞分化和髓鞘形成。我们的结果证明了常见髓鞘疾病中激活素受体信号失调，并揭示了Acvr2a是在整个生命周期中受到损伤后产生髓鞘的新型治疗靶标。Acvr2b表达的增加会隔离配体，从而损害Acvr2a驱动的少突胶质细胞分化和髓鞘形成。我们的结果证明了常见髓鞘疾病中激活素受体信号失调，并揭示了Acvr2a是在整个生命周期中受到损伤后产生髓鞘的新型治疗靶标。Acvr2b表达的增加会隔离配体，从而损害Acvr2a驱动的少突胶质细胞分化和髓鞘形成。我们的结果证明了常见髓鞘疾病中激活素受体信号失调，并揭示了Acvr2a是在整个生命周期中受到损伤后产生髓鞘的新型治疗靶标。