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Stem Cell Reports. 2017 Aug 8;9(2):543-556. doi: 10.1016/j.stemcr.2017.06.014. Epub 2017 Jul 27.

Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development.

Author information

1
Department of Clinical Pharmacology, Institution of Stem Cells and Neuroregeneration, Pharmacy College, Nanjing Medical University, Nanjing 211166, P.R. China; Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: qigangzhou@njmu.edu.cn.
2
Department of Clinical Pharmacology, Institution of Stem Cells and Neuroregeneration, Pharmacy College, Nanjing Medical University, Nanjing 211166, P.R. China.
3
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei Laboratory Animal Research Center, Yonsei University, Seoul 120-749, Korea.
4
Departments of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kyoto 606-850, Japan.
5
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
6
Department of Chinese Medicine, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
7
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015 Zhejiang, P.R. China.
8
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: suhh2@ccf.org.
9
Department of Clinical Pharmacology, Institution of Stem Cells and Neuroregeneration, Pharmacy College, Nanjing Medical University, Nanjing 211166, P.R. China. Electronic address: dyzhu@njmu.edu.cn.

Abstract

The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert-/-) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.

KEYWORDS:

circuit integration; hippocampus; neural development; neural progenitor cells; telomerase

PMID:
28757168
PMCID:
PMC5550029
DOI:
10.1016/j.stemcr.2017.06.014
[Indexed for MEDLINE]
Free PMC Article

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