Chunxue Zhang
Xianjun Liu
Liqiang Zhou
Jiping Liu
Yinan Yao
Juehua Yu
Yuteng Weng
Min Pan
Jie Liu
Zuolin Wang
Yao Sun
Yi Eve Sun
1 Tongji University School of Medicine, Stem Cell Translational Research Center, Tongji Hospital, Shanghai 200065, China;
2 Department of Oral Implantology, School of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, China;
3 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
4 Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China
Funds: 2017BR009 YS.
2014BAI04B07 WZL
This study was supported by China National Key Research and Development Program (2016YFA0100801 YS), and the National Natural Science Foundation of China (Grant Nos. 8133030 YS and 31620103904 YS), and grants:2016YFC102705 YS
TJ1504219036 WZL
81470715 YS
Received Date: 2017-06-22
Rev Recd Date:2017-06-29
Abstract
Abstract
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 both in vitro and in 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.Keywords: blood-brain barrier,
dentin matrix protein1,
glycosylation,
astrocyte,
cell adhesion,
proteoglycan
PDF全文下载地址:
http://www.protein-cell.org/article/exportPdf?id=c6101d47-e257-4ea2-8586-d968100391cc&language=en
