Deficiency of the clock gene Bmal1 affects neural progenitor cell migration

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. Electronic supplementary material The online version of this article (10.1007/s00429-018-1775-1) contains supplementary material, which is available to authorized users.

Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

“…Importantly, actin polymerization shows a circadian rhythm in the liver (Gerber et al, ). Moreover, in Bmal1‐deficient neuronal progenitor cells, the formation of filopodia, actin‐dependent cell protrusions in migrating cells, is changed (Ali et al, ). These findings suggest that the regulation of actin dynamics by the molecular clockwork might be a more general mechanism.…”

“…Bmal1−/− and Bmal1+/+ littermates at age P0 ( n = 3 of each genotype) were decapitated and brains were quickly removed. Cultures of neural stem cells were prepared as previously described (Ali et al, ). Briefly, the meninges, the brain stem, and the cerebellum were removed.…”

“…Bmal1−/− mice have a significantly reduced lifespan and show signs of accelerated ageing such as sarcopenia, cataracts, less subcutaneous fat, organ shrinkage by 16-18 weeks of age, presumably as a consequence of highly elevated levels of reactive oxygen species (ROS) (Kondratov, Kondratova, Gorbacheva, Vykhovanets, & Antoch, 2006). Moreover, Bmal1−/− mice exhibit severe cognitive deficits (Kondratov et al, 2006;Kondratova, Dubrovsky, Antoch, & Kondratov, 2010) and impaired adult neurogenesis (Ali et al, 2015;Ali et al, 2018;Bouchard-Cannon, Mendoza-Viveros, Yuen, Kaern, & Cheng, 2013). In the brain of 10-15 weeks old Bmal1−/− mice astrocytosis starts to develop, as evidenced by an increased expression of glial fibrillary acidic protein (GFAP) (Musiek et al, 2013) and by the age of 24 weeks, synaptic terminals are degenerated and cortical functional connectivity is affected (Musiek et al, 2013).…”

Impact of Targeted Deletion of the Circadian Clock Gene Bmal1 in Excitatory Forebrain Neurons on Adult Neurogenesis and Olfactory Function

“…Our previous studies in Bmal1-/mice showed higher oxidative stress in the neurogenic niches of the SGZ and the SVZ/RMS, which was associated with impaired adult neurogenesis [9,10]. However, in Bmal1 fKO mice, there was no increase in oxidative stress in the respective neurogenic niches.…”

“…As conventional Bmal1-deficiency affects NPC migration in the RMS and the OB presumably, as a consequence of oxidative stress [10], we analyzed 8-OH(d)g-IR in the RMS and the OB of Bmal1 fKO mice (n = 4 per genotype). 8-OH(d)g-IR was not different in both the RMS (p = 0.7) and the GCL (p = 0.2) ( Figure 5).…”