TY - JOUR
T1 - Adaptor protein LNK is a negative regulator of brain neural stem cell proliferation after stroke
AU - Ahlenius, Henrik
AU - Devaraju, Karthikeyan
AU - Monni, Emanuela
AU - Oki, Koichi
AU - Wattananit, Somsak
AU - Darsalia, Vladimer
AU - Iosif, Robert E.
AU - Torper, Olof
AU - Wood, James C.
AU - Braun, Sebastian
AU - Jagemann, Lucas
AU - Nuber, Ulrike A.
AU - Englund, Elisabet
AU - Jacobsen, Sten Eirik W.
AU - Lindvall, Olle
AU - Kokaia, Zaal
PY - 2012/4/11
Y1 - 2012/4/11
N2 - 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 wedemonstrate thatLNKis expressed in NSPCs in the adult mouse andhumanSVZ. LNK -/- mice exhibited increasedNSPCproliferation 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.
AB - 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 wedemonstrate thatLNKis expressed in NSPCs in the adult mouse andhumanSVZ. LNK -/- mice exhibited increasedNSPCproliferation 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.
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U2 - 10.1523/JNEUROSCI.0474-12.2012
DO - 10.1523/JNEUROSCI.0474-12.2012
M3 - Article
C2 - 22496561
AN - SCOPUS:84859520686
VL - 32
SP - 5151
EP - 5164
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 15
ER -