title: Adaptor protein LNK is a negative regulator of brain neural stem cell proliferation after stroke.
abstract: Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain.
authors.affiliation: Laboratory of Neural Stem Cell Biology and Therapy, Lund University Hospital, SE-221 84 Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ahlenius
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Devaraju
authors.forename: Emanuela
authors.initials: E
authors.lastname: Monni
authors.forename: Koichi
authors.initials: K
authors.lastname: Oki
authors.forename: Somsak
authors.initials: S
authors.lastname: Wattananit
authors.forename: Vladimer
authors.initials: V
authors.lastname: Darsalia
authors.forename: Robert E
authors.initials: RE
authors.lastname: Iosif
authors.forename: Olof
authors.initials: O
authors.lastname: Torper
authors.forename: James C
authors.initials: JC
authors.lastname: Wood
authors.forename: Sebastian
authors.initials: S
authors.lastname: Braun
authors.forename: Lucas
authors.initials: L
authors.lastname: Jagemann
authors.forename: Ulrike A
authors.initials: UA
authors.lastname: Nuber
authors.forename: Elisabet
authors.initials: E
authors.lastname: Englund
authors.forename: Sten-Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: Olle
authors.initials: O
authors.lastname: Lindvall
authors.forename: Zaal
authors.initials: Z
authors.lastname: Kokaia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000963:Antimetabolites; D001921:Brain / Q000166:cytology*; D002545:Brain Ischemia / Q000473:pathology*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018274:Electroporation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D020127:Recovery of Function; D012190:Retroviridae / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology; D020521:Stroke / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000963:Antimetabolites; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D051058:Oncogene Protein v-akt; D001973:Bromodeoxyuridine