The brain generates new cells to replace those lost to injury and age, but only to a very modest degree – nowhere near enough to compensate for the damage that accumulates over a life span. Further, the processes of neurogenesis, the birth and integration of new neurons, decline with age. There is some interest in finding ways to spur greater neurogenesis, as the basis for therapies or enhancement technologies, and here researchers investigate a possible proximate cause of the age-related reduction in the pace at which new neurons are created in brain tissue.



The hippocampus is one neurogenic niche where new neurons arising from neural stem cells (NSCs) are constantly generated throughout life in a process called adult hippocampal neurogenesis. Deficits in this process are observed with aging and are believed to underlie age-related cognitive deficits. However, the molecular identity governing such deficits is not fully understood. A mitotic checkpoint kinase, BubR1, has emerged as a key factor in age-related pathology and lifespan. Whether BubR1 also regulates age-related changes in hippocampal neurogenesis is unknown. Notably, BubR1 is expressed in the postnatal mouse dentate gyrus and is relatively higher in the subgranular zone (SGZ) than the dentate granule layer. In addition, BubR1 is expressed in radial glia-like NSCs (RGCs) and is reduced in an age-dependent manner. We hypothesized that age-dependent regulation of BubR1 plays a possible role in hippocampal neurogenesis.



Using adult BubR1 H/H mice with reduced hippocampal BubR1 levels, we first showed significantly reduced cell proliferation in the SGZ and subventricular zone. Progenitor cell types vulnerable to BubR1 insufficiency included significant reductions in activated RGCs, intermediate progenitor cells (IPCs), and neuroblasts. Subsequently, BubR1 H/H mice exhibited a significant decrease in the density of mature new neurons, while survival of new cells was not affected. Thus, these results indicate that the reduction in hippocampal neurogenesis may result primarily from a decrease in neural progenitor proliferation, rather than affecting survival.



In this study, we have identified several novel functions of BubR1 in the adult brain. First, we show BubR1 level is significantly reduced with age. Given that BubR1 insufficiency contributes to age-related pathology including short lifespan, our findings extend the established function of BubR1 to aging and cognitive decline. Second, BubR1 is primarily known as a key regulator for mitosis. We identify an adult-specific mitotic function of BubR1 in ensuring a precise number of neural progenitors are proliferated and an effective rate of neurogenesis is maintained. Third, we show a critical postmitotic function of BubR1. Rather than affecting cell survival, BubR1 insufficiency impairs neuronal maturation and impairs dendrite morphogenesis. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging-related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age-related cognitive deficits.


Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12594/full



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