Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis

2015-01-13

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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
withcriticallyshorttelomeresyieldreducednumbersofneuronsthat,furthermore,exhibitunderdevelopedneuriticarbors.Geneticdata
indicate that the tumor suppressor protein p53 not only mediates the adverse effects of telomere attrition on proliferation and self-
renewal but it is also involved in preventing normal neuronal differentiation of adult progenitors with dysfunctional telomeres. Inter-
estingly, 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 neurito-
genesis. 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.

notes and highlights
-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.
-Histological analysis
-cell culture
-cell transduction
-immunohistochemistry
-neuritic-dendritic measurements
-Confocal
-RNA isolation and semiquantitative and quantitative PCR analyses

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