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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.

Original publication

DOI

10.1523/JNEUROSCI.0474-12.2012

Type

Journal article

Journal

J Neurosci

Publication Date

11/04/2012

Volume

32

Pages

5151 - 5164

Keywords

Animals, Antimetabolites, Brain, Brain Ischemia, Bromodeoxyuridine, Cell Proliferation, Cell Survival, Cells, Cultured, Chromatin Immunoprecipitation, Electroporation, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Immunohistochemistry, Infarction, Middle Cerebral Artery, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Neural Stem Cells, Oncogene Protein v-akt, Real-Time Polymerase Chain Reaction, Recovery of Function, Retroviridae, STAT1 Transcription Factor, STAT3 Transcription Factor, Stroke, Transcription Factors, Transfection