Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons.
Telomerase, a reverse transcriptase that maintains chromosome ends (telomeres) during successive cell divisions in mitotic cells is present in neuroblasts and early postmitotic embryonic neurons but is absent from adult neurons. The signals that control telomerase levels during development are unknown, as are the functions of telomerase in developing neurons. We now report that telomerase activity and levels of its catalytic subunit telomerase reverse transcriptase (TERT) are increased in embryonic hippocampal neurons by brain-derived neurotrophic factor (BDNF) and a secreted form of beta-amyloid precursor protein (sAPP). BDNF and sAPP promote the survival of the embryonic neurons, and these trophic effects are blocked when TERT production is suppressed using antisense technology. Telomerase is required for the long-term survival of early postmitotic neurons during a time window of approximately 1 week in culture; telomerase is then downregulated and is not required for BDNF and sAPP survival signaling in mature neurons. The increase in telomerase activity and trophic effects of BDNF and sAPP are mediated by phosphatidylinositol-3 kinase and p42/p44 MAP kinases. Our findings demonstrate a requirement for telomerase in the cell survival-promoting actions of BDNF and sAPP in early postmitotic hippocampal neurons, suggesting a previously unknown role for telomerase in mediating the biological actions of neurotrophic factors during brain development.
Fu
Weiming
W
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
Lu
Chengbiao
C
Mattson
Mark P
MP
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D006624:Hippocampus / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019098:Telomerase