Activin receptors regulate the oligodendrocyte lineage in health and disease.
Activin receptors regulate the oligodendrocyte lineage in health and disease.
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DOI：
10.1007/s00401-018-1813-3
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发表时间：
2018-06
影响因子：
12.7
通讯作者：
Miron VE
中科院分区：
文献类型：
--
作者：
Dillenburg A;Ireland G;Holloway RK;Davies CL;Evans FL;Swire M;Bechler ME;Soong D;Yuen TJ;Su GH;Becher JC;Smith C;Williams A;Miron VE
最常见的髓磷脂神经系统疾病包括导致婴儿脑瘫和成人多发性硬化症的围产期脑损伤。尽管这些疾病具有不同的病因，但它们具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髓磷脂缺乏，这方面的临床需求尚未得到满足。在这里，我们揭示了这两种疾病共同的分子病理学是激活素受体的失调，并且激活素受体信号传导是发育和损伤后大部分髓磷脂生成所必需的。通过对少突胶质细胞谱系细胞中所有激活素受体信号传导的组成型条件敲除，我们发现这种信号传导是通过调节少突胶质细胞分化和髓鞘质压缩来实现髓鞘形成所必需的。这些过程被发现依赖于激活素受体亚型 Acvr2a，该亚型在少突胶质细胞分化和发育中的轴突鞘形成以及髓磷脂损伤后表达。在有效的髓磷脂再生过程中，Acvr2a 的上调与 Acvr2b 的下调同时发生，Acvr2b 是一种具有相对较高配体亲和力的受体亚型； Acvr2b 被证明对于激活素受体驱动的少突胶质细胞分化是可有可无的，并且其过度表达足以损害上述配体驱动的反应。分别在人类围产期脑损伤和多发性硬化症组织的髓鞘形成或髓鞘再生活跃区域中，表达 Acvr2a 的少突胶质细胞谱系细胞数量超过表达 Acvr2b 的细胞数量，而在非修复性损伤中，Acvr2b + 细胞增加。因此，我们提出，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磷脂形成。我们的结果证明了常见髓鞘质疾病中激活素受体信号传导失调，并揭示了 Acvr2a 作为整个生命周期损伤后髓鞘质生成的新治疗靶点。本文的在线版本 (10.1007/s00401-018-1813-3) 包含补充材料，可供授权用户使用。
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. The online version of this article (10.1007/s00401-018-1813-3) contains supplementary material, which is available to authorized users.
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DOI：
10.3390/molecules17010315
发表时间：
2011-12-30
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
He JT;Mang J;Mei CL;Yang L;Wang JQ;Xing Y;Yang H;Xu ZX
通讯作者：
Xu ZX
影响因子：
6.4
作者：
Billiards, Saraid S.;Haynes, Robin L.;Kinney, Hannah C.
通讯作者：
Kinney, Hannah C.
影响因子：
64.8
作者：
Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
DOI：
10.1523/jneurosci.2546-10.2010
发表时间：
2010-08-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chew LJ;Coley W;Cheng Y;Gallo V
通讯作者：
Gallo V
DOI：
10.1016/j.cub.2015.07.056
发表时间：
2015-09-21
期刊：
Current biology : CB
影响因子：
--
作者：
Bechler ME;Byrne L;Ffrench-Constant C
通讯作者：
Ffrench-Constant C