title: Soluble cpg15 from Astrocytes Ameliorates Neurite Outgrowth Recovery of Hippocampal Neurons after Mouse Cerebral Ischemia.
abstract: The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody. Furthermore, lentivirus-delivered knockdown of cpg15 expression in mouse hippocampal astrocytes diminishes the dendritic branches and exacerbates injury of neurons in CA1 region after TGI. In addition, treatment with inhibitors of MEK1/2, PI3K, and TrkA decreases, whereas overexpression of p-CREB, but not dp-CREB, increases the expression of cpg15 in U118 or primary cultured astrocytes. Also, it is observed that the Flag-tagged soluble cpg15 from the astrocytes transfected with Flag-tagged cpg15-expressing plasmids adheres to the surface of neuronal bodies and the neurites. In conclusion, our results suggest that the soluble cpg15 from astrocytes induced by ischemia could ameliorate the recovery of the ischemic-injured hippocampal neurons via adhering to the surface of neurons. The upregulated expression of cpg15 in astrocytes may be activated via MAPK and PI3K signal pathways, and regulation of CREB phosphorylation.SIGNIFICANCE STATEMENTNeuronal plasticity plays a crucial role in the amelioration of neurological recovery of ischemic injured brain, which remains a challenge for clinic treatment of cerebral ischemia. cpg15 as a synaptic plasticity-related factor may participate in promoting the recovery process; however, the underlying mechanisms are still largely unknown. The objective of this study is to reveal the function and mechanism of neuronal-specific cpg15 expressed in astrocytes after ischemia induction, in promoting the recovery of injured neurons. Our findings provided new mechanistic insight into the neurological recovery, which might help develop novel therapeutic options for cerebral ischemia via astrocytic-targeting interference of gene expression.
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Jie-Xian
authors.initials: JX
authors.lastname: Hu
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: De-Xin
authors.initials: DX
authors.lastname: Lu
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Ji
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China xhchen@fudan.edu.cn.
authors.forename: Xian-Hua
authors.identifier: 0000-0001-6087-4453
authors.initials: XH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D000071446:Neuronal Outgrowth / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D020127:Recovery of Function / Q000502:physiology; D012995:Solubility
chemical_list: D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C484377:Nrn1 protein, mouse
keywords: astrocytes; cpg15; mouse cerebral ischemia; neurite outgrowth recovery; soluble