title: HMGB1 contributes to regeneration after spinal cord injury in adult zebrafish.
abstract: High mobility group box 1 (HMGB1, also called amphoterin) facilitates neurite outgrowth in early development, yet can exacerbate pathology and inhibit regeneration by inducing adverse neuroinflammation when released from dying cells, suggesting that HMGB1 plays a critical, yet undefined role in neuroregeneration. We explored whether HMGB1 contributes to recovery after complete spinal cord transection in adult zebrafish. Quantitative PCR and in situ hybridization revealed that HMGB1 mRNA levels decreased between 12 h to 11 days after spinal cord injury (SCI), then returned to basal levels by 21 days. Western blot and immunohistological analyses indicated that the time course of HMGB1 protein expression after SCI parallels that of mRNA. Immunofluorescence staining revealed that HMGB1 translocates from nuclei into the cytoplasm of spinal motoneurons at 4 and 12 h (acute stage) following SCI, then accumulates in the nuclei of motoneurons during the ensuing chronic stage (after 6 days following SCI). Immunohistology of transgenic zebrafish, expressing green fluorescent protein in blood vessels, showed enhanced HMGB1 expression in blood vessels in the vicinity of motoneurons. Application of anti-sense HMGB1 morpholinos inhibited locomotor recovery by 34 % and decreased axonal regeneration by 34 % compared to fish treated with a control morpholino. The present study shows that HMGB1 expression increases in both endothelial cells and motoneurons, suggesting that HMGB1 promotes recovery from SCI not only through enhancing neuroregeneration, but also by increasing angiogenesis. The inflammatory effects of HMGB1 are minimized through the decrease in HMGB1 expression during the acute stage.
authors.affiliation: Center for Neuroscience, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.forename: Hong-Chao
authors.initials: HC
authors.lastname: Pan
authors.forename: Stanley Li
authors.initials: SL
authors.lastname: Lin
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Zhang
authors.forename: Heikki
authors.initials: H
authors.lastname: Rauvala
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: Shen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish
chemical_list: D024243:HMGB1 Protein