http://stroke.ahajournals.org/content/48/Suppl_1/A141
Abstract
Background:
Molecular mechanisms underlying stroke-induced neurogenesis have not
been fully investigated. The microRNA 17-92 cluster (miR17-92) regulates
proliferation and differentiation of adult neural progenitor cells
(NPCs). The present study investigated whether the miR17-92 cluster in
NPCs is required for stroke-induced neurogenesis.
Methods and Results: Mice with inducible and conditional knockdown of the miR17-92 cluster in nestin lineage NPCs (nestin-CreERT2/miR17-92-/-,
17-92-cKO, n=9) and wild-type litters (WT, n=9) were treated by
tamoxifen. Administration of tamoxifen resulted in more than 60%
reduction of individual members of the miR-17-92 cluster (miR-17: 1.0 vs
0.4; miR-19a: 1.0 vs 0.3; miR-19b: 1.0 vs 0.2; miR-20a: 1.0 vs 0.4;
miR-92a: 1.0 vs 0.4 fold in WT, p<0.05) in NPCs localized to the
subventricular zone (SVZ). Two days after termination of tamoxifen
treatment, these mice were subjected to permanent right middle cerebral
artery occlusion (MCAO) and sacrificed 28 days post-MCAo. Compared to WT
mice, 17-92-cKO mice exhibited significant (p<0.05) reduction of
proliferation of NPCs measured by the number of Ki67+ cells (226±43 vs 471±100 cells/mm2) and the number of DCX+
neuroblasts (11±2% vs 24±4% ) in the ischemic SVZ. Cultured NPCs
harvested from ischemic cKO mice showed significant (p<0.05)
reduction of BrdU+ cells (37±2% vs 61±4% WT , n=3/group), Tuj1+ neuroblasts (5±0.2% vs 9±0.4% ), GFAP+ cells (33±3% vs 53±2% ), and NG2+
oligodendrocyte progenitor cells (OPCs, 3±0.1% vs 5±0.5%). These in
vivo and in vitro data indicate that reduction of the miR17-92 cluster
suppresses stroke-induced neurogenesis and gliogenesis. Western blot
analysis showed that miR17-92 cKO significantly (p<0.05) increased
and reduced a cytoskeleton-associated protein, Enigma homolog1 (ENH1,
1.6 vs 1.0 fold), and its down-stream transcription factor, inhibitor of
differentiation1 (ID1, 1.0 vs 0.6 fold), respectively. ENH1 is a
putative target of the miR17-92 cluster.
Conclusion:
Our data indicate that the miR17-92 cluster in adult nestin lineage
NPCs is required for stroke-induced neurongenesis and gliogenesis, and
that the miR17-92 cluster possibly targets ENH1/ID1 signaling.
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