Different Requirements of Functional Telomeres in Neural Stem Cells and Terminally Differentiated Neurons

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2017 Apr 22

PMID 28428263

Citations 13

Authors

Anastasia Lobanova

Robert She

Simon Pieraut

Charlie Clapp

Anton Maximov

Eros Lazzerini Denchi

Affiliations

Soon will be listed here.

Abstract

Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans.

Citing Articles

The neuro-protective role of telomerase via TERT/TERF-2 in the acute phase of spinal cord injury.

Chang D, Kim J, Kim H, Kim Y, Kim S, Ha K Eur Spine J. 2023; 32(7):2431-2440.

PMID: 37165116 DOI: 10.1007/s00586-023-07561-3.

Telomeres and Telomerase in the Control of Stem Cells.

Lupatov A, Yarygin K Biomedicines. 2022; 10(10).

PMID: 36289597 PMC: 9598777. DOI: 10.3390/biomedicines10102335.

Stem cells at odds with telomere maintenance and protection.

Penev A, Markiewicz-Potoczny M, Sfeir A, Denchi E Trends Cell Biol. 2022; 32(6):527-536.

PMID: 35063336 PMC: 9106881. DOI: 10.1016/j.tcb.2021.12.007.

Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression.

Pathak G, Wendt F, Levey D, Mecca A, van Dyck C, Gelernter J Hum Mol Genet. 2021; 30(14):1360-1370.

PMID: 33831179 PMC: 8255129. DOI: 10.1093/hmg/ddab102.

The end protection problem-an unexpected twist in the tail.

Ruis P, Boulton S Genes Dev. 2020; 35(1-2):1-21.

PMID: 33361389 PMC: 7778267. DOI: 10.1101/gad.344044.120.

References

Chin L, Artandi S, Shen Q, Tam A, Lee S, Gottlieb G . p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999; 97(4):527-38. DOI: 10.1016/s0092-8674(00)80762-x. View

Rossiello F, Herbig U, Longhese M, Fumagalli M, dAdda di Fagagna F . Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing. Curr Opin Genet Dev. 2014; 26:89-95. PMC: 4217147. DOI: 10.1016/j.gde.2014.06.009. View

McHugh T, Jones M, Quinn J, Balthasar N, Coppari R, Elmquist J . Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science. 2007; 317(5834):94-9. DOI: 10.1126/science.1140263. View

Chan S, Blackburn E . Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci. 2004; 359(1441):109-21. PMC: 1693310. DOI: 10.1098/rstb.2003.1370. View

Dokal I . Dyskeratosis congenita in all its forms. Br J Haematol. 2000; 110(4):768-79. DOI: 10.1046/j.1365-2141.2000.02109.x. View

Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban P . Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet. 1999; 23(1):99-103. DOI: 10.1038/12703. View

Zhang P, Pazin M, Schwartz C, Becker K, Wersto R, Dilley C . Nontelomeric TRF2-REST interaction modulates neuronal gene silencing and fate of tumor and stem cells. Curr Biol. 2008; 18(19):1489-94. PMC: 2576494. DOI: 10.1016/j.cub.2008.08.048. View

Hoyeraal H, Lamvik J, MOE P . Congenital hypoplastic thrombocytopenia and cerebral malformations in two brothers. Acta Paediatr Scand. 1970; 59(2):185-91. DOI: 10.1111/j.1651-2227.1970.tb08986.x. View

Oikawa S . Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging. Environ Health Prev Med. 2011; 10(2):65-71. PMC: 2723656. DOI: 10.1007/BF02897995. View

10.

Harris J, Hirokawa K, Sorensen S, Gu H, Mills M, Ng L . Anatomical characterization of Cre driver mice for neural circuit mapping and manipulation. Front Neural Circuits. 2014; 8:76. PMC: 4091307. DOI: 10.3389/fncir.2014.00076. View

11.

Martinez P, Ferrara-Romeo I, Flores J, Blasco M . Essential role for the TRF2 telomere protein in adult skin homeostasis. Aging Cell. 2014; 13(4):656-68. PMC: 4326939. DOI: 10.1111/acel.12221. View

12.

Zhang P, Furukawa K, Opresko P, Xu X, Bohr V, Mattson M . TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons. J Neurochem. 2006; 97(2):567-81. DOI: 10.1111/j.1471-4159.2006.03779.x. View

13.

Rudolph K, Chang S, Lee H, Blasco M, Gottlieb G, Greider C . Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999; 96(5):701-12. DOI: 10.1016/s0092-8674(00)80580-2. View

14.

Jacobs J, de Lange T . Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol. 2004; 14(24):2302-8. DOI: 10.1016/j.cub.2004.12.025. View

15.

Burgess N, Maguire E, OKeefe J . The human hippocampus and spatial and episodic memory. Neuron. 2002; 35(4):625-41. DOI: 10.1016/s0896-6273(02)00830-9. View

16.

Ballas N, Mandel G . The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol. 2005; 15(5):500-6. DOI: 10.1016/j.conb.2005.08.015. View

17.

Minty F, Thurlow J, Harrison P, Parkinson E . Telomere dysfunction in human keratinocytes elicits senescence and a novel transcription profile. Exp Cell Res. 2008; 314(13):2434-47. DOI: 10.1016/j.yexcr.2008.05.007. View

18.

Cardin R, Piciocchi M, Tieppo C, Maddalo G, Zaninotto G, Mescoli C . Oxidative DNA damage in Barrett mucosa: correlation with telomeric dysfunction and p53 mutation. Ann Surg Oncol. 2013; 20 Suppl 3:S583-9. DOI: 10.1245/s10434-013-3043-1. View

19.

Smogorzewska A, Karlseder J, Holtgreve-Grez H, Jauch A, de Lange T . DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol. 2002; 12(19):1635-44. DOI: 10.1016/s0960-9822(02)01179-x. View

20.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View