Telomere protection mechanisms change during neurogenesis and neuronal maturation: Newly generated neurons are hypersensitive to telomere and DNA damage
Journal
Journal of Neuroscience
Journal Volume
27
Journal Issue
14
Pages
3722-3733
Date Issued
2007
Author(s)
Cheng A.
Shin-ya K.
Wan R.
Miura T.
Tang H.
Khatri R.
Gleichman M.
Ouyang X.
Liu D.
Park H.-R.
Chiang J.Y.
Mattson M.P.
Abstract
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. Copyright ? 2007 Society for Neuroscience.
SDGs
Other Subjects
DNA; histone; telomerase; telomeric repeat binding factor 2; telomestatin; animal cell; animal experiment; animal tissue; apoptosis; article; cell differentiation; cell maturation; cell proliferation; cell protection; DNA damage; enzyme deficiency; female; mitosis; mouse; nervous system development; nonhuman; priority journal; protein expression; protein modification; sensitivity analysis; stem cell; telomere; Animals; Cell Differentiation; Cell Line; Cells, Cultured; Cerebral Cortex; DNA Damage; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pregnancy; Telomere
Type
journal article