Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis

Abstract

Proliferation in the subependymal zone (SEZ) and neurogenesis in the olfactory bulb decline in the forebrain of telomerase-deficient mice. The present work reveals additional effects of telomere shortening on neuronal differentiation, as adult multipotent progenitors with critically short telomeres yield reduced numbers of neurons that, furthermore, exhibit underdeveloped neuritic arbors. Genetic data indicate that the tumor suppressor protein p53 not only mediates the adverse effects of telomere attrition on proliferation and selfrenewal but it is also involved in preventing normal neuronal differentiation of adult progenitors with dysfunctional telomeres. Interestingly, progenitor cells with short telomeres obtained from fetal brains do not exhibit any replicative defects but also fail to acquire a fully mature neuritic arbor, demonstrating cell cycle-independent effects of telomeres on neuronal differentiation. The negative effect of p53 on neuritogenesis is mechanistically linked to its cooperation with the Notch pathway in the upregulation of small GTPase RhoA kinases, Rock1 and Rock2, suggesting a potential link between DNA damage and the Notch signaling pathway in the control of neuritogenesis. We also show that telomerase expression is downregulated in the SEZ of aging mice leading to telomere length reductions in neurosphere-forming cells and deficient neurogenesis and neuritogenesis. Our results suggest that age-related deficits could be caused partly by dysfunctional telomeres and demonstrate that p53 is a central modulator of adult neurogenesis, regulating both the production and differentiation of postnatally generated olfactory neurons.

Uniform, optimal signal processing of mapped deep-sequencing data

“…6e). Notably, Notch1 targets that were predicted by using the de novo motif highlighted control of telomerase activity and cell cycle, both functions previously linked to Notch signaling 43,44 ( Fig. 6f).…”

“…Furthermore, transcription factor functions can also be inferred from the same data, through analysis of enriched target-gene annotations. Notably, we uncovered an ACTACAnnTCCCAnRR motif in the promoters of mouse forebrain-specific genes, which may mediate the known effects of Notch signaling on telomerase activity and cell cycle control during brain development 43,44 . Although the exact degree of heterogeneity in e11.5 forebrain (or in e14.5 anatomical structures) is not known, it is possible that other samples could be even more heterogeneous, and therefore refractory to the methods described here.…”

Notch signaling in the brain: In good and bad times

“…Another investigation using mouse fibroblasts, lacking the ubiquitin ligase Fbw7, showed that Notch activation is linked to p53 upregulation in mediating cell cycle arrest (Ishikawa et al, 2008). A mutual positive feedback of p53 on Notch activity has also been recently reported: p53, by sensing DNA damage, activates an apoptosis cascade in neuronal stem cells and contributes, together with Notch, to reducing neurites' length through the action of the small GTPase RhoA kinases, Rock1 and Rock2 (Ferron et al, 2009) (Fig. 3).…”

The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging

“…Specifically, telomerase activity has been an active area of research, and promoting telomerase activity increases neurogenesis in vitro and in vivo (Caporaso et al 2003;Ferron et al 2009;Jaskelioff et al 2011;Liu et al 2012). These studies suggest that reversing the declines in telomerase activity can prevent aging-associated declines in stem-cell function and cognition.…”