Phosphoinositide 3-kinase promotes adult subventricular neuroblast migration after stroke.
Rodent adult subventricular zone (SVZ)-derived progenitor cells abandon the rostral migratory stream (RMS)/olfactory complex postmiddle cerebral artery occlusion (MCAo) and migrate into compromised tissue, possibly playing a role in brain recovery. Using SVZ tissue explants from the adult rat, we investigated the role of the phosphoinositide 3-kinase (PI3K) signal transduction pathway in the migration of SVZ cells. Stroke significantly (P <.01) increased migratory speed (198 +/- 39 microm/day) of neuroblasts out of the SVZ explants compared with the speed (99 +/- 20 microm/day) in the normal SVZ (nSVZ) explants within the first 3 days of incubation. Three-dimensional laser scanning confocal microscopy revealed formation of neuroblast encompassing chain-like astrocyte structures extruding from both normal and stroke explants. Western blots showed that stroke SVZ (sSVZ) explants increased Akt phosphorylation. Treatment of sSVZ explants with the selective PI3K inhibitor LY294002 significantly (P <.01) attenuated neuroblast migration and Akt phosphorylation, whereas treatment with LY294002 did not affect the number of bromodeoxyuridine (BrdU)- and caspase-3-immunoreactive cells, indicating that stroke-enhanced neuroblast migration is independent of cell proliferation and survival. PI3K catalyzes phosphatidylinositol-3,4,5-triphosphate (PIP(3)) which facilitates Akt phosphorylation. Thus, our data demonstrate that the PI3K/Akt signal transduction pathway mediates neuroblast migration after stroke.
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Mark
M
Katakowski
Zheng Gang
ZG
Zhang
Jieli
J
Chen
Ruilan
R
Zhang
Ying
Y
Wang
Hao
H
Jiang
Lijie
L
Zhang
Adam
A
Robin
Yi
Y
Li
Michael
M
Chopp
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002552:Cerebral Ventricles / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D002633:Chemotaxis / Q000502:physiology; D008297:Male; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase