N-Acetylglucosamine 6-O-sulfotransferase-1 is required for brain keratan sulfate biosynthesis and glial scar formation after brain injury.
Keratan sulfate (KS) is a glycosaminoglycan composed of repeating disaccharide units with sulfate residues at the C6 positions of galactose and N-acetylglucosamine (GlcNAc). The N-acetylglucosamine 6-O-sulfotransferase(s) (GlcNAc6ST) involved in the synthesis of KS in the central nervous system (CNS) has long been unidentified. Here, we report that a deficiency of GlcNAc6ST-1 leads to loss of 5D4-reactive brain KS and reduction of glial scar formation after cortical stab injury in mice. During the development of mice deficient in GlcNAc6ST-1, KS expression in the brain was barely detectable with the KS-specific antibody 5D4. The reactivity of 5D4 antibody with protein tyrosine phosphatase zeta (PTPzeta), a KS proteoglycan (KSPG), was abolished in the deficient mice. In adults, brain injury induced 5D4-reactive KS synthesis in the wounded area in wild-type (WT) mice but not in the deficient mice. Glial scar is formed via the accumulation of reactive astrocytes and is a major obstacle to axonal regeneration by injured neurons. Reactive astrocytes appeared to similar extents in the two genotypes, but they accumulated in the wounded area to a lesser extent in the deficient mice. Consequently, the deficient mice exhibited a marked reduction of scarring and enhanced neuronal regeneration after brain injury. These findings highlight the indispensable role of GlcNAc6ST-1 in brain KS biosynthesis and glial scar formation after brain injury.
Zhang
Haoqian
H
Department of Biochemistry, Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Muramatsu
Takashi
T
Murase
Atsushi
A
Yuasa
Shigeki
S
Uchimura
Kenji
K
Kadomatsu
Kenji
K
D000117:Acetylglucosamine / Q000737:chemistry; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D024141:Collagen Type IV / Q000032:analysis / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D007632:Keratan Sulfate / Q000096:biosynthesis* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015238:Sulfotransferases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors
D024141:Collagen Type IV; D005904:Glial Fibrillary Acidic Protein; D007632:Keratan Sulfate; D015238:Sulfotransferases; D000117:Acetylglucosamine