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.