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Cited by 17Neurogenesis and neuroplasticity mechanismsMultiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration Mechanisms

N‐myc downstream regulated family member 1 (NDRG1) is enriched in myelinating oligodendrocytes and impacts myelin degradation in response to demyelination

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Marechal, Damien, Dansu, David K., Castro, Kamilah, Patzig, Julia, Magri, Laura, Inbar, Benjamin, Gacias, Mar, Moyon, Sarah +1 more·2022·Glia
DOI 10.1002/glia.24108PMC PMC8753715
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Abstract

The N‐myc downstream regulated gene family member 1 (NDRG1) is a gene whose mutation results in peripheral neuropathy with central manifestations. While most of previous studies characterized NDRG1 role in Schwann cells, the detection of central nervous system symptoms and the identification of NDRG1 as a gene silenced in the white matter of multiple sclerosis brains raise the question regarding its role in oligodendrocytes. Here, we show that NDRG1 is enriched in oligodendrocytes and myelin preparations, and we characterize its expression using a novel reporter mouse (TgNdrg1‐EGFP). We report NDRG1 expression during developmental myelination and during remyelination after cuprizone‐induced demyelination of the adult corpus callosum. The transcriptome of Ndrg1‐EGFP+ cells further supports the identification of late myelinating oligodendrocytes, characterized by expression of genes regulating lipid metabolism and bioenergetics. We also generate a lineage specific conditional knockout (Olig1cre/+;Ndrg1fl/fl) line to study its function. Null mice develop normally, and despite similar numbers of progenitor cells as wild type, they have fewer mature oligodendrocytes and lower levels of myelin proteins than controls, thereby suggesting NDRG1 as important for the maintenance of late myelinating oligodendrocytes. In addition, when control and Ndrg1 null mice are subject to cuprizone‐induced demyelination, we observe a higher degree of demyelination in the mutants. Together these data identify NDRG1 as an important molecule for adult myelinating oligodendrocytes, whose decreased levels in the normal appearing white matter of human MS brains may result in greater susceptibility of myelin to damage.

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Research works printed but not linked: 55

  1. Anders S, & Huber W. (2010). Differential expression analysis for sequence count data. Genome Biol, 11(10), R106. doi: 10.1186/gb-2010-11-10-r106 20979621 PMC3218662 · DOI · Paper page
  2. Berger P, Sirkowski EE, Scherer SS, & Suter U. (2004). Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom. Neurobiol Dis, 17(2), 290– 299. doi: 10.1016/j.nbd.2004.07.014 15474366 · DOI
  3. Berger P, Young P, & Suter U. (2002). Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics, 4(1), 1– 15. doi: 10.1007/s10048-002-0130-z 12030326 · DOI
  4. Blaes J, Weiler M, Sahm F, Hentschel B, Osswald M, Czabanka M, … Wick W. (2014). NDRG1 prognosticates the natural course of disease in WHO grade II glioma. J Neurooncol, 117(1), 25– 32. doi: 10.1007/s11060-013-1357-2 24395351 · DOI
  5. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, … Barres BA (2008). A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci, 28(1), 264– 278. doi: 10.1523/jneurosci.4178-07.2008 18171944 PMC6671143 · DOI · Paper page
  6. Cangul H. (2004). Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet, 5, 27. doi: 10.1186/1471-2156-5-27 15341671 PMC518960 · DOI
  7. Chen B, Nelson DM, & Sadovsky Y. (2006). N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. J Biol Chem, 281(5), 2764– 2772. doi: 10.1074/jbc.M507330200 16314423 · DOI
  8. Chen Z, Zhang D, Yue F, Zheng M, Kovacevic Z, & Richardson DR (2012). The iron chelators Dp44mT and DFO inhibit TGF-β-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1). J Biol Chem, 287(21), 17016– 17028. doi: 10.1074/jbc.M112.350470 22453918 PMC3366822 · DOI
  9. Dixon KM, Lui GY, Kovacevic Z, Zhang D, Yao M, Chen Z, … Richardson DR (2013). Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells. Br J Cancer, 108(2), 409– 419. doi: 10.1038/bjc.2012.582 23287991 PMC3566801 · DOI
  10. Echaniz-Laguna A, Degos B, Bonnet C, Latour P, Hamadouche T, Lévy N, & Leheup B. (2007). NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement. Neuromuscul Disord, 17(2), 163– 168. doi: 10.1016/j.nmd.2006.10.002 17142040 · DOI
  11. Eden E, Navon R, Steinfeld I, Lipson D, & Yakhini Z. (2009). GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics, 10, 48. doi: 10.1186/1471-2105-10-48 19192299 PMC2644678 · DOI · Paper page
  12. Ellen TP, Ke Q, Zhang P, & Costa M. (2008). NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis, 29(1), 2– 8. doi: 10.1093/carcin/bgm200 17916902 · DOI
  13. Enserink JM (2015). Sumo and the cellular stress response. Cell Div, 10, 4. doi: 10.1186/s13008-015-0010-1 26101541 PMC4476178 · DOI
  14. Fotovati A, Abu-Ali S, Kage M, Shirouzu K, Yamana H, & Kuwano M. (2011). N-myc downstream-regulated gene 1 (NDRG1) a differentiation marker of human breast cancer. Pathol Oncol Res, 17(3), 525– 533. doi: 10.1007/s12253-010-9342-y 21221878 · DOI
  15. García-Martínez JM, & Alessi DR (2008). mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J, 416(3), 375– 385. doi: 10.1042/bj20081668 18925875 · DOI · Paper page
  16. Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, … Heintz N. (2003). A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature, 425(6961), 917– 925. doi: 10.1038/nature02033 14586460 · DOI · Paper page
  17. Hay N, & Sonenberg N. (2004). Upstream and downstream of mTOR. Genes Dev, 18(16), 1926– 1945. doi: 10.1101/gad.1212704 15314020 · DOI · Paper page
  18. Hughes EG, Orthmann-Murphy JL, Langseth AJ, & Bergles DE (2018). Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex. Nat Neurosci, 21(5), 696– 706. doi: 10.1038/s41593-018-0121-5 29556025 PMC5920726 · DOI · Paper page
  19. Hunter M, Bernard R, Freitas E, Boyer A, Morar B, Martins IJ, … Kalaydjieva L. (2003). Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease. Hum Mutat, 22(2), 129– 135. doi: 10.1002/humu.10240 12872253 · DOI
  20. Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD, … Casaccia P. (2014). Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci, 17(1), 121– 130. doi: 10.1038/nn.3588 24270187 PMC3934491 · DOI
  21. Jahn O, Siems SB, Kusch K, Hesse D, Jung RB, Liepold T, … Werner HB (2020). The CNS Myelin Proteome: Deep Profile and Persistence After Post-mortem Delay. Front Cell Neurosci, 14, 239. doi: 10.3389/fncel.2020.00239 32973451 PMC7466725 · DOI
  22. Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, … Thomas PK (2000). N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet, 67(1), 47– 58. doi: 10.1086/302978 10831399 PMC1287101 · DOI
  23. Kalaydjieva L, Nikolova A, Turnev I, Petrova J, Hristova A, Ishpekova B, … Thomas PK (1998). Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings. Brain, 121 (Pt 3), 399– 408. doi: 10.1093/brain/121.3.399 9549516 · DOI
  24. Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, … Bergles DE (2013). Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci, 16(5), 571– 579. doi: 10.1038/nn.3357 23542689 PMC3637847 · DOI · Paper page
  25. King RH, Chandler D, Lopaticki S, Huang D, Blake J, Muddle JR, … Kalaydjieva L. (2011). Ndrg1 in development and maintenance of the myelin sheath. Neurobiol Dis, 42(3), 368– 380. doi: 10.1016/j.nbd.2011.01.030 21303696 · DOI
  26. Klinghoffer RA, Hamilton TG, Hoch R, & Soriano P. (2002). An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during development. Dev Cell, 2(1), 103– 113. doi: 10.1016/s1534-5807(01)00103-4 11782318 · DOI
  27. Koutsoudaki PN, Skripuletz T, Gudi V, Moharregh-Khiabani D, Hildebrandt H, Trebst C, & Stangel M. (2009). Demyelination of the hippocampus is prominent in the cuprizone model. Neurosci Lett, 451(1), 83– 88. doi: 10.1016/j.neulet.2008.11.058 19084049 · DOI · Paper page
  28. Larocca JN, & Norton WT (2007). Isolation of myelin. Curr Protoc Cell Biol, Chapter 3, Unit3.25. doi: 10.1002/0471143030.cb0325s33 18228513 · DOI
  29. Le Bras B, Chatzopoulou E, Heydon K, Martínez S, Ikenaka K, Prestoz L, … Thomas JL (2005). Oligodendrocyte development in the embryonic brain: the contribution of the plp lineage. Int J Dev Biol, 49(2–3), 209– 220. doi: 10.1387/ijdb.041963bl 15906234 · DOI
  30. Le NT, & Richardson DR (2004). Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood, 104(9), 2967– 2975. doi: 10.1182/blood-2004-05-1866 15251988 · DOI
  31. Lee JE, & Kim JH (2015). SUMO modification regulates the protein stability of NDRG1. Biochem Biophys Res Commun, 459(1), 161– 165. doi: 10.1016/j.bbrc.2015.02.090 25712528 · DOI
  32. Li B, Ruotti V, Stewart RM, Thomson JA, & Dewey CN (2010). RNA-Seq gene expression estimation with read mapping uncertainty. Bioinformatics, 26(4), 493– 500. doi: 10.1093/bioinformatics/btp692 20022975 PMC2820677 · DOI · Paper page
  33. Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD, & Rowitch DH (2002). Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell, 109(1), 75– 86. doi: 10.1016/s0092-8674(02)00678-5 11955448 · DOI
  34. Ma W, Na M, Tang C, Wang H, & Lin Z. (2015). Overexpression of N-myc downstream-regulated gene 1 inhibits human glioma proliferation and invasion via phosphoinositide 3-kinase/AKT pathways. Mol Med Rep, 12(1), 1050– 1058. doi: 10.3892/mmr.2015.3492 25777142 PMC4438970 · DOI
  35. Magri L, Gacias M, Wu M, Swiss VA, Janssen WG, & Casaccia P. (2014). c-Myc-dependent transcriptional regulation of cell cycle and nucleosomal histones during oligodendrocyte differentiation. Neuroscience, 276, 72– 86. doi: 10.1016/j.neuroscience.2014.01.051 24502923 PMC4294794 · DOI
  36. Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, … Kuwano M. (2006). Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res, 66(12), 6233– 6242. doi: 10.1158/0008-5472.CAN-06-0183 16778198 · DOI
  37. McCaig C, Potter L, Abramczyk O, & Murray JT (2011). Phosphorylation of NDRG1 is temporally and spatially controlled during the cell cycle. Biochem Biophys Res Commun, 411(2), 227– 234. doi: 10.1016/j.bbrc.2011.06.092 21708134 · DOI
  38. Melotte V, Qu X, Ongenaert M, van Criekinge W, de Bruïne AP, Baldwin HS, & van Engeland M. (2010). The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J, 24(11), 4153– 4166. doi: 10.1096/fj.09-151464 20667976 · DOI
  39. Moyon S, Huynh JL, Dutta D, Zhang F, Ma D, Yoo S, … Casaccia P. (2016). Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage. Cell Rep, 15(4), 748– 760. doi: 10.1016/j.celrep.2016.03.060 27149841 PMC5063656 · DOI
  40. Okamoto Y, Goksungur MT, Pehlivan D, Beck CR, Gonzaga-Jauregui C, Muzny DM, … Lupski JR (2014). Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D. Genet Med, 16(5), 386– 394. doi: 10.1038/gim.2013.155 24136616 PMC4224029 · DOI
  41. Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, & Miyata T. (2004). Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves. Mol Cell Biol, 24(9), 3949– 3956. doi: 10.1128/mcb.24.9.3949-3956.2004 15082788 PMC387740 · DOI
  42. Okuda T, Kokame K, & Miyata T. (2008). Differential expression patterns of NDRG family proteins in the central nervous system. J Histochem Cytochem, 56(2), 175– 182. doi: 10.1369/jhc.7A7323.2007 17998568 PMC2324175 · DOI
  43. Pietiäinen V, Vassilev B, Blom T, Wang W, Nelson J, Bittman R, … Ikonen E. (2013). NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation. J Cell Sci, 126(Pt 17), 3961– 3971. doi: 10.1242/jcs.128132 23813961 · DOI
  44. Schonkeren SL, Massen M, van der Horst R, Koch A, Vaes N, & Melotte V. (2019). Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system. Neurogenetics, 20(4), 173– 186. doi: 10.1007/s10048-019-00587-0 31485792 PMC6754360 · DOI
  45. Sevinsky CJ, Khan F, Kokabee L, Darehshouri A, Maddipati KR, & Conklin DS (2018). NDRG1 regulates neutral lipid metabolism in breast cancer cells. Breast Cancer Res, 20(1), 55. doi: 10.1186/s13058-018-0980-4 29898756 PMC6001025 · DOI
  46. Silvestroff L, Bartucci S, Pasquini J, & Franco P. (2012). Cuprizone-induced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination. Exp Neurol, 235(1), 357– 367. doi: 10.1016/j.expneurol.2012.02.018 22421533 · DOI
  47. Skripuletz T, Gudi V, Hackstette D, & Stangel M. (2011). De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histol Histopathol, 26(12), 1585– 1597. doi: 10.14670/hh-26.1585 21972097 · DOI
  48. Skripuletz T, Lindner M, Kotsiari A, Garde N, Fokuhl J, Linsmeier F, … Stangel M. (2008). Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. Am J Pathol, 172(4), 1053– 1061. doi: 10.2353/ajpath.2008.070850 18349131 PMC2276412 · DOI · Paper page
  49. Spassky N, Goujet-Zalc C, Parmantier E, Olivier C, Martinez S, Ivanova A, … Thomas JL (1998). Multiple restricted origin of oligodendrocytes. J Neurosci, 18(20), 8331– 8343. 9763477 PMC6792828
  50. Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS, … Liang P. (2004). NDRG1 is necessary for p53-dependent apoptosis. J Biol Chem, 279(47), 48930– 48940. doi: 10.1074/jbc.M400386200 15377670 · DOI
  51. Sun B, Chu D, Li W, Chu X, Li Y, Wei D, & Li H. (2009). Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients. J Neurooncol, 94(2), 213– 219. doi: 10.1007/s11060-009-9859-7 19337694 · DOI
  52. Sun J, Zhang D, Bae DH, Sahni S, Jansson P, Zheng Y, … Richardson DR (2013). Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors. Carcinogenesis, 34(9), 1943– 1954. doi: 10.1093/carcin/bgt163 23671130 · DOI
  53. Werner HB, Kuhlmann K, Shen S, Uecker M, Schardt A, Dimova K, … Nave KA (2007). Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J Neurosci, 27(29), 7717– 7730. doi: 10.1523/jneurosci.1254-07.2007 17634366 PMC2676101 · DOI
  54. Yuan X, Chittajallu R, Belachew S, Anderson S, McBain CJ, & Gallo V. (2002). Expression of the green fluorescent protein in the oligodendrocyte lineage: a transgenic mouse for developmental and physiological studies. J Neurosci Res, 70(4), 529– 545. doi: 10.1002/jnr.10368 12404507 · DOI
  55. Zhang AH, Rao JN, Zou T, Liu L, Marasa BS, Xiao L, … Wang JY (2007). p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion. Am J Physiol Cell Physiol, 293(1), C379– 389. doi: 10.1152/ajpcell.00547.2006 17442733 · DOI

Cited by

Sorted by citations

Authors
Marechal, D., Dansu, D. K., Castro, K., Patzig, J., Magri, L., Inbar, B., Gacias, M., Moyon, S., & Casaccia, P.
Affiliations
  • Neuroscience Initiative, Advanced Science Research Center, CUNY New York City New York USA
  • The Graduate Center, CUNY (US)
  • City University of New York (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Casaccia, Patrizia
ORCID
Venue
Glia
Publisher
Wiley
Published
2021-10-23
Volume
70
Issue
2
Pages
321-336
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.24108
PMC
PMC8753715
OpenAlex
W3209064320
Cited by
17
References
3
Citations by year
2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 2
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Glia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (5F31NS098575, R35‐NS111604)
  • National Multiple Sclerosis Society (FG‐1507‐04996, FG‐1804‐30361, FG‐2070, RG‐4890)
  • Rockefeller University (HHSN271200723701C, N01NS02331)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
NDRG1, myelinating oligodendrocytes, myelin degradation, demyelination, remyelination, cuprizone, multiple sclerosis, oligodendrocyte lineage, myelination, lipid metabolism, bioenergetics, oligodendrocyte precursor cells, normal-appearing white matter, conditional knockout mice
MeSH terms
Animals, Cuprizone, Family, Mice, Inbred C57BL, Multiple Sclerosis, Myelin Sheath, Oligodendroglia, Mice

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