Article

Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJIncreasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443: 448-452

Howard Hughes Medical Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
Nature (Impact Factor: 42.35). 10/2006; 443(7110):448-52. DOI: 10.1038/nature05091
Source: PubMed

ABSTRACT Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells. It has been proposed that this is at least partially caused by the senescence of progenitors with age; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.

Download full-text

Full-text

Available from: Ricardo Pardal, Aug 23, 2015
0 Followers
 · 
141 Views
  • Source
    • "Notably, at the Flt3 locus, H3K27me3 was increased and expression decreased (Figure S3G), consistent with the diminished lymphoid differentiation potential of aged HSCs. One well-known target of the PcG family during aging is Cdkn2a (encoding p16 INK4a ), which showed progressive loss of H3K27me3-associated repression and increased expression with aging in neural stem cells (Molofsky et al., 2006). Increased Cdkn2a is considered a primary indicator of cellular senescence in virtually all tissues in mice and humans (Ló pez-Otín et al., 2013). "
  • Source
    • "Levels of p16 increase with age in several tissues in vivo (Zindy et al., 1997; Nielsen et al., 1999; Krishnamurthy et al., 2004). Moreover, aging p16-null mice display greater preservation of proliferation of progenitor cells in pancreatic islets, bone marrow, and some neural tissues (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006). Based on such observations, p16 has been proposed as a biomarker and potential effector of aging and is widely used as a marker of cellular senescence, in vitro and in vivo. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cyclin-dependent kinase (Cdk) inhibitor p16(Ink4a) (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit-amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16-mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 12/2014; 14(1). DOI:10.1111/acel.12279 · 5.94 Impact Factor
  • Source
    • "NSCs generate rapidly proliferating neural progenitor cells that ultimately differentiate to produce thousands of new neurons each day in the adult mammalian brain (Abrous et al., 2005). Neurogenesis declines with age (Molofsky et al., 2006; Pekcec et al., 2008; Knoth et al., 2010) and is impaired by various types of stressors, such as stress hormones (Mirescu and Gould, 2006), and inflammation in regions of the brain (Monje et al., 2003). Natriuretic peptides hormones, which stimulate branch formation and induce axon outgrowth, have wide influence on the development and function of the nervous system in the embryonic and adult mammal (Zhao and Ma, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural stem cells (NSCs) play an essential role in development of the central nervous system. Endoplasmic reticulum (ER) stress induces neuronal death. After neuronal death, neurogenesis is generally enhanced to repair the damaged regions. However, it is unclear whether ER stress directly affects neurogenesis-related processes such as neuronal differentiation and dendrite outgrowth. We evaluated whether neuronal differentiation and dendrite outgrowth were regulated by HRD1, a ubiquitin ligase that was induced under mild conditions of tunicamycin-induced ER stress. Neurons were differentiated from mouse embryonic carcinoma P19 cells by using retinoic acid. The differentiated cells were cultured for 8 days with or without tunicamycin and HRD1 knockdown. The ER stressor led to markedly increased levels of ER stress. ER stress increased the expression levels of neuronal marker βIII-tubulin in 8-day-differentiated cells. However, the neurites of dendrite marker microtubule-associated protein-2 (MAP-2)-positive cells appeared to retract in response to ER stress. Moreover, ER stress markedly reduced the dendrite length and MAP-2 expression levels, whereas it did not affect the number of surviving mature neurons. In contrast, HRD1 knockdown abolished the changes in expression of proteins such as βIII-tubulin and MAP-2. These results suggested that ER stress caused aberrant neuronal differentiation from NSCs followed by the inhibition of neurite outgrowth. These events may be mediated by increased HRD1 expression. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 09/2014; 92(9). DOI:10.1002/jnr.23389 · 2.73 Impact Factor
Show more