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The Journal of Neuroscience, April 4, 2007, 27(14):3722-3733; doi:10.1523/JNEUROSCI.0590-07.2007

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Development/Plasticity/Repair
Telomere Protection Mechanisms Change during Neurogenesis and Neuronal Maturation: Newly Generated Neurons Are Hypersensitive to Telomere and DNA Damage

Aiwu Cheng,¹ Kazuo Shin-ya,² Ruiqian Wan,¹ Sung-chun Tang,^1,3 Takumi Miura,¹ Hongyang Tang,¹ Rina Khatri,¹ Marc Gleichman,¹ Xin Ouyang,¹ Dong Liu,¹ Hae-Rong Park,² Jeffrey Y. Chiang,⁴ and Mark P. Mattson^1,5

¹Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, ²Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, 113-8656, Japan, ³Stroke Center, Neurology Department, National Taiwan University Hospital, Taipei, Taiwan, ROC 100, ⁴Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892, and ⁵Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to either of the following: Aiwu Cheng, National Institute on Aging, Gerontology Research Center 4F16, 5600 Nathan Shock Drive, Baltimore, MD 21224, Email: chengai{at}grc.nia.nih.gov; or Mark P. Mattson, National Institute on Aging, Gerontology Research Center 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, Email: mattsonm{at}grc.nia.nih.gov

Telomeres are DNA–protein complexes at the ends of eukaryotic chromosomes that play an important role in maintaining the integrity of the genome. In proliferative stem cells and cancer cells, telomere length is maintained by telomerase, and telomere structure and functions are regulated by telomere-associated proteins. We find that telomerase levels are high in embryonic cortical neural progenitor cells (NPCs) and low in newly generated neurons (NGNs) and mature neurons (MNs). In contrast, telomere repeat-binding factor 2 (TRF2) expression is undetectable in early brain development in vivo and in cultured NPCs and is expressed at progressively higher levels as NPCs cease proliferation and differentiate into postmitotic neurons. The telomere-disrupting agent telomestatin induces a DNA damage response and apoptosis in NGNs (which have low levels of TRF2 and telomerase), whereas NPCs (which have high levels of telomerase) and MNs (which have high levels of TRF2) are resistant to telomere damage. Overexpression of TRF2 in NGNs protects them against death induced by telomestatin and other DNA-damaging agents. Knockdown of TRF2 expression in MNs and knock-out of telomerase reverse transcriptase in NPCs increased their sensitivity to telomere- and DNA-damaging agents but did not affect the vulnerability of NGNs. These findings suggest that TRF2 and telomerase function as distinct telomere protection mechanisms during the processes of neurogenesis and neuronal maturation and that hypersensitivity of NGNs to telomere damage results from relative deficiencies of both telomerase and TRF2.

Key words: apoptosis; DNA; histone modification; neurogenesis; neuronal death; neuronal progenitor cell

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Received July 20, 2006; accepted Feb. 20, 2007.

Correspondence should be addressed to either of the following: Aiwu Cheng, National Institute on Aging, Gerontology Research Center 4F16, 5600 Nathan Shock Drive, Baltimore, MD 21224, Email: chengai{at}grc.nia.nih.gov; or Mark P. Mattson, National Institute on Aging, Gerontology Research Center 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, Email: mattsonm{at}grc.nia.nih.gov

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