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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Forebrain glutamatergic neuron-specific Ctcf deletion induces reactive microgliosis and astrogliosis with neuronal loss in adult mouse hippocampus

  • Kwak, Ji-Hye (Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University) ;
  • Lee, Kyungmin (Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University)
  • Received : 2020.12.02
  • Accepted : 2021.01.22
  • Published : 2021.06.30
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Abstract

CCCTC-binding factor (CTCF), a zinc finger protein, is a transcription factor and regulator of chromatin structure. Forebrain excitatory neuron-specific CTCF deficiency contributes to inflammation via enhanced transcription of inflammation-related genes in the cortex and hippocampus. However, little is known about the long-term effect of CTCF deficiency on postnatal neurons, astrocytes, or microglia in the hippocampus of adult mice. To address this, we knocked out the Ctcf gene in forebrain glutamatergic neurons (Ctcf cKO) by crossing Ctcf-floxed mice with Camk2a-Cre mice and examined the hippocampi of 7.5-10-month-old male mice using immunofluorescence microscopy. We found obvious neuronal cell death and reactive gliosis in the hippocampal cornu ammonis (CA)1 in 7.5-10-month-old cKO mice. Prominent rod-shaped microglia that participate in immune surveillance were observed in the stratum pyramidale and radiatum layer, indicating a potential increase in inflammatory mediators released by hippocampal neurons. Although neuronal loss was not observed in CA3, and dentate gyrus (DG) CTCF depletion induced a significant increase in the number of microglia in the stratum oriens of CA3 and reactive microgliosis and astrogliosis in the molecular layer and hilus of the DG in 7.5-10-month-old cKO mice. These results suggest that long-term Ctcf deletion from forebrain excitatory neurons may contribute to reactive gliosis induced by neuronal damage and consequent neuronal loss in the hippocampal CA1, DG, and CA3 in sequence over 7 months of age.

Keywords

Acknowledgement

This study was supported by the National Research Foundation (NRF) of Korea grants funded by the Korean government (MSIP) [NRF- 2019R1F1A1063932] to K.L.

References

  1. Ong CT and Corces VG (2014) CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet 15, 234-246 https://doi.org/10.1038/nrg3663
  2. Moore JM, Rabaia NA, Smith LE et al (2012) Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos. PLoS One 7, e34915 https://doi.org/10.1371/journal.pone.0034915
  3. Watson LA, Wang X, Elbert A, Kernohan KD, Galjart N and Berube NG (2014) Dual effect of CTCF loss on neuroprogenitor differentiation and survival. J Neurosci 34, 2860-2870 https://doi.org/10.1523/JNEUROSCI.3769-13.2014
  4. Gregor A, Oti M, Kouwenhoven EN et al (2013) De novo mutations in the genome organizer CTCF cause intellectual disability. Am J Hum Genet 93, 124-131 https://doi.org/10.1016/j.ajhg.2013.05.007
  5. Iossifov I, O'Roak BJ, Sanders SJ et al (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216-221 https://doi.org/10.1038/nature13908
  6. Sams DS, Nardone S, Getselter D et al (2016) Neuronal CTCF is necessary for basal and experience-dependent gene regulation, memory formation, and genomic structure of BDNF and Arc. Cell Rep 17, 2418-2430 https://doi.org/10.1016/j.celrep.2016.11.004
  7. Kim S, Yu NK, Shim KW et al (2018) Remote memory and cortical synaptic plasticity require neuronal CCCTC-binding factor (CTCF). J Neurosci 38, 5042-5052 https://doi.org/10.1523/JNEUROSCI.2738-17.2018
  8. Gorman AM (2008) Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12, 2263-2280 https://doi.org/10.1111/j.1582-4934.2008.00402.x
  9. McGill BE, Barve RA, Maloney SE et al (2018) Abnormal microglia and enhanced inflammation-related gene transcription in mice with conditional deletion of Ctcf in Camk2a-Cre-expressing neurons. J Neurosci 38, 200-219 https://doi.org/10.1523/JNEUROSCI.0936-17.2017
  10. Kumamoto K, Iguchi T, Ishida R, Uemura T, Sato M and Hirotsune S (2017) Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning. Biol Open 6, 1041-1055 https://doi.org/10.1242/bio.025999
  11. Gavrieli Y, Sherman Y and Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119, 493-501 https://doi.org/10.1083/jcb.119.3.493
  12. Nagata S (2000) Apoptotic DNA fragmentation. Exp Cell Res 256, 12-18 https://doi.org/10.1006/excr.2000.4834
  13. Lana D, Ugolini F, Wenk GL, Giovannini MG, Zecchi-Orlandini S and Nosi D (2019) Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell-cell interglial interaction. FASEB J 33, 4007-4020 https://doi.org/10.1096/fj.201801539r
  14. Wanner IB, Anderson MA, Song B et al (2013) Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci 33, 12870-12886 https://doi.org/10.1523/JNEUROSCI.2121-13.2013
  15. Kwak JH, Kim S, Yu NK et al (2020) Loss of the neuronal genome organizer and transcription factor CTCF induces neuronal death and reactive gliosis in the anterior cingulate cortex. Genes Brain Behav 20, e12701
  16. Au NPB and Ma CHE (2017) Recent advances in the study of bipolar/rod-shaped microglia and their roles in neurodegeneration. Front Aging Neurosci 9, 128 https://doi.org/10.3389/fnagi.2017.00128
  17. Jonas RA, Yuan TF, Liang YX, Jonas JB, Tay DK and Ellis-Behnke RG (2012) The spider effect: morphological and orienting classification of microglia in response to stimuli in vivo. PLoS One 7, e30763 https://doi.org/10.1371/journal.pone.0030763
  18. Bachstetter AD, Van Eldik LJ, Schmitt FA et al (2015) Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 3, 32 https://doi.org/10.1186/s40478-015-0209-z
  19. De Souza RA, Islam SA, McEwen LM et al (2016) DNA methylation profiling in human Huntington's disease brain. Hum Mol Genet 25, 2013-2030 https://doi.org/10.1093/hmg/ddw076
  20. Gallagher MD, Posavi M, Huang P et al (2017) A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression. Am J Hum Genet 101, 643-663 https://doi.org/10.1016/j.ajhg.2017.09.004
  21. Yang Y, Quitschke WW, Vostrov AA and Brewer GJ (1999) CTCF is essential for up-regulating expression from the amyloid precursor protein promoter during differentiation of primary hippocampal neurons. J Neurochem 73, 2286-2298 https://doi.org/10.1046/j.1471-4159.1999.0732286.x
  22. Heath H, Ribeiro de Almeida C, Sleutels F et al (2008) CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J 27, 2839-2850 https://doi.org/10.1038/emboj.2008.214
  23. Madisen L, Zwingman TA, Sunkin SM et al (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13, 133-140 https://doi.org/10.1038/nn.2467
  24. Seo H and Lee K (2019) Cell-specific expression of Epac2 in the subventricular and subgranular zones. Mol Brain 12, 113 https://doi.org/10.1186/s13041-019-0537-1
  25. Park SW, Jun YW, Choi HE et al (2019) Deciphering the molecular mechanisms underlying the plasma membrane targeting of PRMT8. BMB Rep 52, 601-606 https://doi.org/10.5483/bmbrep.2019.52.10.272