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19.10.2018 | Original Article Open Access

Deficiency of the clock gene Bmal1 affects neural progenitor cell migration

Zeitschrift:
Brain Structure and Function
Autoren:
Amira A. H. Ali, Beryl Schwarz-Herzke, Shakila Mir, Benita Sahlender, Marion Victor, Boris Görg, Martin Schmuck, Katharina Dach, Ellen Fritsche, Andreas Kremer, Charlotte von Gall
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00429-018-1775-1) contains supplementary material, which is available to authorized users.
Amira A. H. Ali and Beryl Schwarz-Herzke contributed equally to this work.

Abstract

We demonstrate the impact of a disrupted molecular clock in Bmal1-deficient (Bmal1−/−) mice on migration of neural progenitor cells (NPCs). Proliferation of NPCs in rostral migratory stream (RMS) was reduced in Bmal1−/− mice, consistent with our earlier studies on adult neurogenesis in hippocampus. However, a significantly higher number of NPCs from Bmal1−/− mice reached the olfactory bulb as compared to wild-type littermates (Bmal1+/+ mice), indicating a higher migration velocity in Bmal1−/− mice. In isolated NPCs from Bmal1−/− mice, not only migration velocity and expression pattern of genes involved in detoxification of reactive oxygen species were affected, but also RNA oxidation of catalase was increased and catalase protein levels were decreased. Bmal1+/+ migration phenotype could be restored by treatment with catalase, while treatment of NPCs from Bmal1+/+ mice with hydrogen peroxide mimicked Bmal1−/− migration phenotype. Thus, we conclude that Bmal1 deficiency affects NPC migration as a consequence of dysregulated detoxification of reactive oxygen species.

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Zusatzmaterial
Figure S1. Representative photomicrographs of cresyl violet-stained parasagittal mouse brain section indicating the analyzed anatomical structures. SVZ, subventricular zone; pRMS, proximal limb of rostral migratory stream, dRMS, distal limb of rostral migratory stream; GCL, granular cell layer; MCL, mitral cell layer, EPL, external plexiform layer, GL, glomerular layer. Scale bar, 200µm (TIF 31213 KB)
429_2018_1775_MOESM1_ESM.tif
Figure S2. Representative photomicrographs of a Bmal1+/+ neurospheres. (a) Overview of a neurosphere. The migrating cells were identified as PAS-NCAM-immunoreactive neural progenitors (green) with NucBlue counterstaining (blue) Scale bar= 50 µm (b) perimeter of a neurosphere with migrating PAS-NCAM-immunoreactive neural progenitors (green) at higher magnification. Scale bar= 20 µm. (c) perimeter of a neurosphere with migrating doublecortin (DCX, red)-immunoreactive neural progenitor cells with co-labeling for glial fibrillary acidic protein (GFAP, green) and NucBlue counterstaining (blue) (TIF 27032 KB)
429_2018_1775_MOESM2_ESM.tif
Figure S3. Bmal1 deficiency does not affect the total number of proliferating cells reaching the olfactory bulb within 31 days. Representative photomicrographs and quantification of BrdU+ cells (brawn stained cells, black arrows) in the olfactory bulb of Bmal1+/+ mice (+/+) and Bmal1-/- mice (-/-). Values are shown as mean +/- SEM. n=5 mice per genotype. Scale bars = 50 µm. Counterstaining with cresyl violet was used to show anatomical location (TIF 26364 KB)
429_2018_1775_MOESM3_ESM.tif
Figure S4. Cytoplasmic 8-OH(d)G immunoreaction represents oxidized RNA. Representative photomicrographs of NPCs from BMAL1-/- mice cytochemically stained with a DNA-marker NucBlue (blue) and immunocytochemically with 8-OH(d)G-antibody (red) 24 h after seeding and treatment with vehicle (control), 10µg/ml DNase I, or 5 µg/µl RNase. Scale bars= 20 µm (TIF 25365 KB)
429_2018_1775_MOESM4_ESM.tif
Figure S5. Treatment of NPCs from Bmal1-/- mice with hydrogen peroxide and NPCs from Bmal1+/+ mice with catalase does not affect migration. a) Representative photomicrographs of NPCs from Bmal1-/- mice (-/-) treated with vehicle (control) or 80 µM hydrogen peroxide (H2O2) for 24 h. Scale bar: 200 µm. (b) Time course of migration distance and velocity is not different between vehicle (control) and treatment with 80 µM H2O2 during the first 24 h after seeding. n=3 mice per group. (c) Representative photomicrographs of NPCs from Bmal1++ mice (+/+) treated with vehicle (control) or 500 U/ml catalase (catalase) for 24 h. Scale bar: 200 µm. (d) Time course of migration distance and velocity is not different between vehicle (control) and treatment with 500 U/ml catalase during the first 24 h after seeding. n=3 mice per group (TIF 30992 KB)
429_2018_1775_MOESM5_ESM.tif
Figure S6 Treatment of NPCs derived from Bmal1-/- mice with N-acetylcysteine does not affect migration. Neurospheres derived from Bmal1-/- mice were seeded in migration medium supplemented with different concentrations of N-acetylcysteine or vehicle (control) and continuously recorded during the first 24 h (TIF 25289 KB)
429_2018_1775_MOESM6_ESM.tif
Appendix Video 1 Migration of NPCs derived from Bmal1 +/+ mice. Neurospheres were recorded continuously during the first 24 hours after culture in migration medium. Time interval between phase-contrast images at 100x magnification was 60 min (AVI 38712 KB)
Appendix Video 2 Migration of NPCs derived from Bmal1 -/- mice. Neurospheres were recorded continuously during the first 24 hours after seeding in migration medium. Time interval between phase-contrast images at 100x magnification was 60 min (AVI 38574 KB)
Appendix Video 3 Migration of NPCs derived from Bmal1 +/+ mice in the presence of hydrogen peroxide. Neurospheres were recorded continuously during the first 24 hours after seeding in migration medium in the presence of 80 µM hydrogen peroxide (H 2O 2). Time interval between phase contrast images at 100x magnification was 60 min (AVI 38634 KB)
Appendix Video 4 Migration of NPCs derived from Bmal1 -/- mice in the presence of catalase. Neurospheres were recorded continuously during the first 24 hours after seeding in migration medium in the presence of 500 U/ml catalase. Time interval between phase contrast images at 100x magnification was 60 min (AVI 38072 KB)
Literatur
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