title: Splicing factor NSSR1 reduces neuronal injury after mouse transient global cerebral ischemia.
abstract: This study focuses on the function of NSSR1, a splicing factor, in neuronal injury in the ischemic mouse brain using the transient global cerebral ischemic mouse model and the cultured cells treated with oxygen-glucose deprivation (OGD). The results showed that the cerebral ischemia triggers the expression of NSSR1 in hippocampal astrocytes, predominantly the dephosphorylated NSSR1 proteins, and the Exon3 inclusive NCAM-L1 variant and the Exon4 inclusive CREB variant. While in the hippocampus of astrocyte-specific NSSR1 conditional knockdown (cKD) mice, where cerebral ischemia no longer triggers NSSR1 expression in astrocytes, the expression of Exon3 inclusive NCAM-L1 variant and Exon4 inclusive CREB variant were no longer triggered as well. In addition, the injury of hippocampal neurons was more severe in astrocyte-specific NSSR1 cKD mice compared with in wild-type mice after brain ischemia. Of note, the culture media harvested from the astrocytes with overexpression of NSSR1 or the Exon3 inclusive NCAM-L1 variant, or Exon4 inclusive CREB variant were all able to reduce the neuronal injury induced by OGD. The results provide the evidence demonstrating that: (1) Splicing factor NSSR1 is a new factor involved in reducing ischemic injury. (2) Ischemia induces NSSR1 expression in astrocytes, not in neurons. (3) NSSR1-mediated pathway in astrocytes is required for reducing ischemic neuronal injury. (4) NCAM-L1 and CREB are probably mediators in NSSR1-mediated pathway. In conclusion, our results suggest for the first time that NSSR1 may provide a novel mechanism for reducing neuronal injury after ischemia, probably through regulation on alternative splicing of NCAM-L1 and CREB in astrocytes.
authors: State Key Laboratory of Medical Neurobiology and Laboratory of Genomic Physiology, Institutes of Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors: Yao
authors: Y
authors: Qi
authors: Ya
authors: Y
authors: Li
authors: Shi-Chao
authors: SC
authors: Cui
authors: Jing-Jing
authors: JJ
authors: Zhao
authors: Xiao-Yan
authors: XY
authors: Liu
authors: Chun-Xia
authors: CX
authors: Ji
authors: Feng-Yan
authors: FY
authors: Sun
authors: Ping
authors: P
authors: Xu
authors: Xian-Hua
authors: XH
authors: Chen
mesh_terms: D000818:Animals; D019002:CD56 Antigen / Q000235:genetics / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D000860:Hypoxia / Q000473:pathology; D047468:Immunoprecipitation; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019002:CD56 Antigen; D018797:Cell Cycle Proteins; C485446:Fusip1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; C501063:Ncam1 protein, mouse; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; D050882:CREB-Binding Protein; D005947:Glucose
keywords: CREB; NCAM-L1; alternative splicing; astrocytes; expression