Dicer, a miRNA biogenesis protein, in adult neural stem cells regulates hypothalamic neurogenesis after stroke

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Conference Proceeding

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Introduction: The hypothalamus regulates the neuroendocrine system. Hypothalamic neurogenesis is localized to the arcuate nucleus (AR) close to the third ventricle (3V) and to the bottom of the 3V in the median eminence (ME). Molecular mechanisms, in particular miRNAs, in regulating hypothalamic neurogenesis remain unknown. Dicer processes precursor miRNAs into mature miRNAs. Using a transgenic mouse line with an inducible and conditional ablation of Dicer in adult neural stem cells (NST), we tested the hypothesis that Dicer regulates stroke-increased hypothalamic neurogenesis. Methods and Results: Using a NST reporter mouse line (Ascl1-CreERT2: Tomatoflox/flox ), we found that NST were present in the AR and the ME. Tamoxifen was administered to mice (n=32) with conditional ablation of Dicer (Dicer/Cko) in NTSs (Ascl1- CreERT2: Dicerflox/flox) to knockout Dicer. Mice were then subjected to focal cerebral ischemia and wild-type mice (n=26) were used as control. Double and triple immunofluorescent staining with 3D confocal microscopic analysis was performed to quantify proliferation and phenotypes of NST. In wild-type mice, stroke significantly (P<0.05) increased BrdU+ NST in the AR (52 ± 3 cells/mm2 vs 40 ± 4 no-stroke) and the ME (45 cells/mm2 ± 4 vs 29 ± 4 no-stroke) 14 days after stroke. The increased proliferating NST were associated with substantial augmentation of newly generated neurons (BrdU+/NeuN+ cells) in the AR (6 ± 1% vs 3 ± 0.4%, no-stroke) and in the ME (5 ± 1% vs 2 ± 0.3%, no-stroke) 30 days after stroke. These data indicate that stroke increases hypothalamic neurogenesis. However, compared to wild-type ischemic mice, ischemic Dicer/Cko mice exhibited significant (p<0.01) reduction of BrdU+ NTS in the AR (41 ± 4) and in the ME (33 ± 4) 14 days after stroke, and significant (p<0.01) decreases of newly generated neurons in the AR (4 ± 0.6%) and in the ME (3 ± 0.5%) 30 days after stroke. Ablation of Dicer in NTS of mice without stroke also resulted in significant reduction of proliferating NST (23 ± 2 cells/mm2 AR, 17 ± 3 ME) and newly generated neurons (2 ± 0.4% AR, 1 ± 0.2 ME) compared to non-ischemic wild-type mice. Conclusion: Our data provide first evidence that Dicer regulates adult hypothalamic neurogenesis under physiological and ischemic conditions.




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