Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity.
Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity.
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牙本质基质蛋白 1 的糖基化是星形胶质细胞成熟和 BBB 完整性的新关键元素
DOI：
10.1007/s13238-017-0449-8
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发表时间：
2018-03
期刊：
影响因子：
21.1
通讯作者：
Sun YE
中科院分区：
文献类型：
--
作者：
Jing B;Zhang C;Liu X;Zhou L;Liu J;Yao Y;Yu J;Weng Y;Pan M;Liu J;Wang Z;Sun Y;Sun YE
血脑屏障（BBB）是内皮细胞和星形胶质细胞之间形成的紧密边界，它将大脑与大多数病原体以及循环中的神经毒素分开并保护大脑。然而，参与 BBB 形成的详细分子参与者尚不完全清楚。牙本质基质蛋白 1 (DMP1)-蛋白多糖 (PG) 已知参与骨骼和牙本质的矿化，也在包括大脑在内的软组织中表达，功能未知。在本研究中，我们报道 DMP1-PG 在脑星形胶质细胞中表达并在 BBB 单位中富集。 DMP1 唯一的糖基化位点是小鼠蛋白质 N 末端结构域中的丝氨酸 89 (S89)。具有 DMP1 点突变的突变小鼠将 S89 变为甘氨酸 (S89G)，完全消除了蛋白质的糖基化，表现出严重的血脑屏障破坏。另一种 DMP1 突变小鼠缺乏 DMP1 C 端结构域，但表现出正常的 BBB 功能。 S89G-DMP1星形胶质细胞的极性被破坏，细胞间粘附松弛。通过一系列分析，我们发现 DMP1 糖基化对于星形胶质细胞的体外和体内成熟至关重要。 S89G-DMP1 突变星形胶质细胞无法表达水通道蛋白 4，并且层粘连蛋白和 ZO1 表达减少，从而导致 BBB 破坏。有趣的是，在巢蛋白启动子驱动下，小鼠大脑中野生型DMP1-PG的过度表达使层粘连蛋白和ZO1表达升高至野生型水平以上，并且可以有效抵抗静脉注射甘露醇诱导的BBB可逆性开放。综上所述，我们的研究不仅揭示了一种调节 BBB 形成的新元件，即 DMP1-PG，而且还为 DMP1-PG 赋予了新功能。
The blood-brain barrier (BBB) is a tight boundary formed between endothelial cells and astrocytes, which separates and protects brain from most pathogens as well as neural toxins in circulation. However, detailed molecular players involved in formation of BBB are not completely known. Dentin matrix protein 1 (DMP1)-proteoglycan (PG), which is known to be involved in mineralization of bones and dentin, is also expressed in soft tissues including brain with unknown functions. In the present study, we reported that DMP1-PG was expressed in brain astrocytes and enriched in BBB units. The only glycosylation site of DMP1 is serine89 (S89) in the N-terminal domain of the protein in mouse. Mutant mice with DMP1 point mutations changing S89 to glycine (S89G), which completely eradicated glycosylation of the protein, demonstrated severe BBB disruption. Another breed of DMP1 mutant mice, which lacked the C-terminal domain of DMP1, manifested normal BBB function. The polarity of S89G-DMP1 astrocytes was disrupted and cell-cell adhesion was loosened. Through a battery of analyses, we found that DMP1 glycosylation was critically required for astrocyte maturation bothin vitroandin vivo. S89G-DMP1 mutant astrocytes failed to express aquaporin 4 and had reduced laminin and ZO1 expression, which resulted in disruption of BBB. Interestingly, overexpression of wild-type DMP1-PG in mouse brain driven by the nestin promoter elevated laminin and ZO1 expression beyond wild type levels and could effectively resisted intravenous mannitol-induced BBB reversible opening. Taken together, our study not only revealed a novel element, i.e., DMP1-PG, that regulated BBB formation, but also assigned a new function to DMP1-PG.
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DOI：
10.1038/nrneurol.2015.119
发表时间：
2015-08
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Tarasoff-Conway JM;Carare RO;Osorio RS;Glodzik L;Butler T;Fieremans E;Axel L;Rusinek H;Nicholson C;Zlokovic BV;Frangione B;Blennow K;Ménard J;Zetterberg H;Wisniewski T;de Leon MJ
通讯作者：
de Leon MJ
影响因子：
30.8
作者：
Lorenz-Depiereux, Bettina;Bastepe, Murat;Strom, Tim M.
通讯作者：
Strom, Tim M.
牙本质基质蛋白 1 的糖基化对于成骨至关重要。
影响因子：
4.6
作者：
Sun Y;Weng Y;Zhang C;Liu Y;Kang C;Liu Z;Jing B;Zhang Q;Wang Z
通讯作者：
Wang Z
DOI：
10.1038/jcbfm.2015.76
发表时间：
2015-07
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Sweeney MD;Sagare AP;Zlokovic BV
通讯作者：
Zlokovic BV
DOI：
10.1159/000151373
发表时间：
2009
期刊：
Cells, tissues, organs
影响因子：
--
作者：
Peng T;Huang B;Sun Y;Lu Y;Bonewald L;Chen S;Butler WT;Feng JQ;D'Souza RN;Qin C
通讯作者：
Qin C