Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity

doi:10.1007/s13238-017-0449-8

Protein Cell

2018, Vol. 9

Issue (3) : 298-309 https://doi.org/10.1007/s13238-017-0449-8

RESEARCH ARTICLE

Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity

Bo Jing¹, Chunxue Zhang¹, Xianjun Liu¹, Liqiang Zhou¹, Jiping Liu¹, Yinan Yao¹, Juehua Yu¹, Yuteng Weng², Min Pan², Jie Liu¹, Zuolin Wang²(

), Yao Sun²(

), Yi Eve Sun^1,^3,⁴(

)

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

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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

Corresponding Author(s): Zuolin Wang,Yao Sun,Yi Eve Sun

Issue Date: 21 March 2018

Cite this article:

Bo Jing,Chunxue Zhang,Xianjun Liu, et al. Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity[J]. Protein Cell, 2018, 9(3): 298-309.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-017-0449-8
https://academic.hep.com.cn/pac/EN/Y2018/V9/I3/298

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