Deficiency of the clock gene Bmal1 affects neural progenitor cell migration

Amira A H Ali,Benita Sahlender,Andreas Kremer,Beryl Schwarz-Herzke,Boris Görg,Charlotte Von Gall,Martin Schmuck,Katharina Dach,Ellen Fritsche,Shakila Mir,Marion Victor

doi:10.1007/s00429-018-1775-1

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.

Highlights

Neurogenesis plays an important role in neuronal plasticity even in the adult brain
The percentage of cells co-labeled with BrdU and DCX was significantly higher in Bmal1−/− mice as compared to B mal1+/+ mice in both, the granule cell layer (P = 0.028, n = 4 mice per genotype) (Fig. 2c) and the glomerular layer (P = 0.028, n = 4 mice per genotype) (Fig. 2d) of the olfactory bulb
We show for the first time, that proliferation and migration of neural progenitor cells (NPCs) in this neurogenic niche is affected in mice with a targeted deletion of the core clock gene Bmal1

Summary

Introduction

Neurogenesis plays an important role in neuronal plasticity even in the adult brain. The subventricular zone (SVZ) of the lateral ventricles represents the most extensive neurogenic niches within the adult brain (Lois and Alvarez-Buylla 1994; Lim and Alvarez-Buylla 2016). It gives rise to neural progenitor cells (NPCs) which generate primarily committed neural progenitor that migrate tangentially along the rostral extension of the SVZ toward the olfactory bulb, forming the rostral migratory stream (RMS) (Lois and Alvarez-Buylla 1994; Doetsch and Alvarez-Buylla 1996; Jankovski and Sotelo 1996; Gritti et al 2002; Lois et al 1996). Within the RMS, NPCs form chains and continue to proliferate while migrating (Gritti et al 2002; Wichterle et al 1997) In mice, this considerable distance from the SVZ to the olfactory bulb of up to 5 mm is traversed by NPCs within 4–6 days (Lois and Alvarez-Buylla 1994). In the white matter of the olfactory bulb, the NPCs detach from the chains and

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Conclusion