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DCC/netrin-1 regulates cell death in oligodendrocytes after brain injury

Abstract

Hallmark pathological features of brain trauma are axonal degeneration and demyelination because myelin-producing oligodendrocytes (OLs) are particularly vulnerable to injury-induced death signals. To reveal mechanisms responsible for this OL loss, we examined a novel class of “death receptors” called dependence receptors (DepRs). DepRs initiate pro-death signals in the absence of their respective ligand(s), yet little is known about their role after injury. Here, we investigated whether the deleted in colorectal cancer (DCC) DepR contributes to OL loss after brain injury. We found that administration of its netrin-1 ligand is sufficient to block OL cell death. We also show that upon acute injury, DCC is upregulated while netrin-1 is downregulated in perilesional tissues. Moreover, after genetically silencing pro-death activity using DCCD1290N mutant mice, we observed greater OL survival, greater myelin integrity, and improved motor function. Our findings uncover a novel role for the netrin-1/DCC pathway in regulating OL loss in the traumatically injured brain.

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Fig. 1: DCC receptors are expressed by oligodendrocytes (OLs) and are dependent on netrin-1 for survival.
Fig. 2: DCCD1290N mice have reduced OL cell death after CCI injury.
Fig. 3: DCCD1290N mice have improved cortical sparing and myelination after CCI injury.
Fig. 4: DCCD1290N mice have improved locomotor function after CCI injury.
Fig. 5: Schematic model of Netrin-1/DCC receptor function in the injured brain.

Data availability

The data analyzed during this study are included in this published paper and the supplemental data files. Additional supporting data are available from the corresponding authors upon reasonable request.

References

  1. Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2019;130:1080–97.

  2. Daugherty J, Waltzman D, Sarmiento K, Xu L. Traumatic Brain Injury-Related Deaths by Race/Ethnicity, Sex, Intent, and Mechanism of Injury - United States, 2000-2017. MMWR Morb Mortal Wkly Rep. 2019;68:1050–6.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vaishnavi S, Rao V, Fann JR. Neuropsychiatric problems after traumatic brain injury: unraveling the silent epidemic. Psychosomatics 2009;50:198–205.

    Article  PubMed  Google Scholar 

  4. McDonald S, Genova H. The effect of severe traumatic brain injury on social cognition, emotion regulation, and mood. Handb Clin Neurol. 2021;183:235–60.

    Article  PubMed  Google Scholar 

  5. Shah EJ, Gurdziel K, Ruden DM. Mammalian Models of Traumatic Brain Injury and a Place for Drosophila in TBI Research. Front Neurosci. 2019;13:409.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Aravind A, Ravula AR, Chandra N, Pfister BJ. Behavioral Deficits in Animal Models of Blast Traumatic Brain Injury. Front Neurol. 2020;11:990.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shultz SR, McDonald SJ, Corrigan F, Semple BD, Salberg S, Zamani A, et al. Clinical Relevance of Behavior Testing in Animal Models of Traumatic Brain Injury. J Neurotrauma. 2020;37:2381–400.

    Article  PubMed  Google Scholar 

  8. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 2013;136:28–42.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Johnson VE, Stewart W, Smith DH. Axonal pathology in traumatic brain injury. Exp Neurol. 2013;246:35–43.

    Article  CAS  PubMed  Google Scholar 

  10. Filley CM, Kelly JP. White Matter and Cognition in Traumatic Brain Injury. J Alzheimers Dis. 2018;65:345–62.

    Article  PubMed  Google Scholar 

  11. Flygt J, Gumucio A, Ingelsson M, Skoglund K, Holm J, Alafuzoff I, et al. Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells. J Neuropathol Exp Neurol. 2016;75:503–15.

    Article  CAS  PubMed  Google Scholar 

  12. Tsenkina Y, Tapanes SA, Díaz MM, Titus DJ, Gajavelli S, Bullock R, et al. EphB3 interacts with initiator caspases and FHL-2 to activate dependence receptor cell death in oligodendrocytes after brain injury. Brain Commun 2020;2:fcaa175.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bramlett HM, Dietrich WD. Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol. 2002;103:607–14.

    Article  PubMed  Google Scholar 

  14. Flygt J, Djupsjö A, Lenne F, Marklund N. Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat. Eur J Neurosci. 2013;38:2153–65.

    Article  CAS  PubMed  Google Scholar 

  15. Sullivan GM, Mierzwa AJ, Kijpaisalratana N, Tang H, Wang Y, Song SK, et al. Oligodendrocyte lineage and subventricular zone response to traumatic axonal injury in the corpus callosum. J Neuropathol Exp Neurol. 2013;72:1106–25.

    Article  PubMed  Google Scholar 

  16. Mierzwa AJ, Marion CM, Sullivan GM, McDaniel DP, Armstrong RC. Components of myelin damage and repair in the progression of white matter pathology after mild traumatic brain injury. J Neuropathol Exp Neurol. 2015;74:218–32.

    Article  PubMed  Google Scholar 

  17. Marion CM, Radomski KL, Cramer NP, Galdzicki Z, Armstrong RC. Experimental Traumatic Brain Injury Identifies Distinct Early and Late Phase Axonal Conduction Deficits of White Matter Pathophysiology, and Reveals Intervening Recovery. J Neurosci. 2018;38:8723–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305–8.

    Article  CAS  PubMed  Google Scholar 

  19. Knoblach SM, Fan L, Faden AI. Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment. J Neuroimmunol. 1999;95:115–25.

    Article  CAS  PubMed  Google Scholar 

  20. Beer R, Franz G, Schöpf M, Reindl M, Zelger B, Schmutzhard E, et al. Expression of Fas and Fas ligand after experimental traumatic brain injury in the rat. J Cereb Blood Flow Metab. 2000;20:669–77.

    Article  CAS  PubMed  Google Scholar 

  21. Qiu J, Whalen MJ, Lowenstein P, Fiskum G, Fahy B, Darwish R, et al. Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J Neurosci. 2002;22:3504–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang X, Graham SH, Kochanek PM, Marion DW, Nathaniel PD, Watkins SC, et al. Caspase-8 expression and proteolysis in human brain after severe head injury. Faseb J. 2003;17:1367–9.

    Article  CAS  PubMed  Google Scholar 

  23. Lotocki G, Alonso OF, Dietrich WD, Keane RW. Tumor necrosis factor receptor 1 and its signaling intermediates are recruited to lipid rafts in the traumatized brain. J Neurosci. 2004;24:11010–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Raghupathi R. Cell death mechanisms following traumatic brain injury. Brain Pathol. 2004;14:215–22.

    Article  PubMed  Google Scholar 

  25. Bermpohl D, You Z, Lo EH, Kim HH, Whalen MJ. TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice. J Cereb Blood Flow Metab. 2007;27:1806–18.

    Article  CAS  PubMed  Google Scholar 

  26. Shohami E, Ginis I, Hallenbeck JM. Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev. 1999;10:119–30.

    Article  CAS  PubMed  Google Scholar 

  27. Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–57.

    Article  PubMed  Google Scholar 

  28. Xiong Y, Mahmood A, Chopp M. Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs. 2009;14:67–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharm Sci. 2010;31:596–604.

    Article  CAS  PubMed  Google Scholar 

  30. Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci. 2014;15:1216–36.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Dang B, Chen W, He W, Chen G. Rehabilitation Treatment and Progress of Traumatic Brain Injury Dysfunction. Neural Plast. 2017;2017:1582182.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rana A, Singh S, Sharma R, Kumar A. Traumatic Brain Injury Altered Normal Brain Signaling Pathways: Implications for Novel Therapeutics Approaches. Curr Neuropharmacol. 2019;17:614–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bonilla C, Zurita M. Cell-Based Therapies for Traumatic Brain Injury: Therapeutic Treatments and Clinical Trials. Biomedicines. 2021;9:669.

  34. Mehlen P, Rabizadeh S, Snipas SJ, Assa-Munt N, Salvesen GS, Bredesen DE. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 1998;395:801–4.

    Article  CAS  PubMed  Google Scholar 

  35. Rodrigues S, De Wever O, Bruyneel E, Rooney RJ, Gespach C. Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. Oncogene 2007;26:5615–25.

    Article  CAS  PubMed  Google Scholar 

  36. Mehlen P, Guenebeaud C. Netrin-1 and its dependence receptors as original targets for cancer therapy. Curr Opin Oncol. 2010;22:46–54.

    Article  CAS  PubMed  Google Scholar 

  37. Krimpenfort P, Song JY, Proost N, Zevenhoven J, Jonkers J, Berns A. Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours. Nature 2012;482:538–41.

    Article  CAS  PubMed  Google Scholar 

  38. Goldschneider D, Mehlen P. Dependence receptors: a new paradigm in cell signaling and cancer therapy. Oncogene 2010;29:1865–82.

    Article  CAS  PubMed  Google Scholar 

  39. Wu S, Guo X, Zhou J, Zhu X, Chen H, Zhang K, et al. High expression of UNC5B enhances tumor proliferation, increases metastasis, and worsens prognosis in breast cancer. Aging (Albany NY). 2020;12:17079–98.

    Article  CAS  PubMed  Google Scholar 

  40. Lourenço FC, Galvan V, Fombonne J, Corset V, Llambi F, Müller U, et al. Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production. Cell Death Differ. 2009;16:655–63.

    Article  PubMed  Google Scholar 

  41. Chen G, Kang SS, Wang Z, Ahn EH, Xia Y, Liu X, et al. Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer’s disease pathologies. Sci Adv. 2021;7:eabe4499.

  42. Jasmin M, Ahn EH, Voutilainen MH, Fombonne J, Guix C, Viljakainen T, et al. Netrin-1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson’s disease features. Embo J. 2021;40:e105537.

    Article  CAS  PubMed  Google Scholar 

  43. Wetzel-Smith MK, Hunkapiller J, Bhangale TR, Srinivasan K, Maloney JA, Atwal JK, et al. A rare mutation in UNC5C predisposes to late-onset Alzheimer’s disease and increases neuronal cell death. Nat Med. 2014;20:1452–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qu Y, Zhao J, Wang Y, Gao Z. Silencing ephrinB3 improves functional recovery following spinal cord injury. Mol Med Rep. 2014;9:1761–6.

    Article  CAS  PubMed  Google Scholar 

  45. Tsenkina Y, Ricard J, Runko E, Quiala-Acosta MM, Mier J, Liebl DJ. EphB3 receptors function as dependence receptors to mediate oligodendrocyte cell death following contusive spinal cord injury. Cell Death Dis. 2015;6:e1922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Theus MH, Ricard J, Bethea JR, Liebl DJ. EphB3 limits the expansion of neural progenitor cells in the subventricular zone by regulating p53 during homeostasis and following traumatic brain injury. Stem Cells. 2010;28:1231–42.

    Article  CAS  PubMed  Google Scholar 

  47. Theus MH, Ricard J, Glass SJ, Travieso LG, Liebl DJ. EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury. Cell Death Dis. 2014;5:e1207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Assis-Nascimento P, Tsenkina Y, Liebl DJ. EphB3 signaling induces cortical endothelial cell death and disrupts the blood-brain barrier after traumatic brain injury. Cell Death Dis. 2018;9:7.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mehlen P, Thibert C. Dependence receptors: between life and death. Cell Mol Life Sci. 2004;61:1854–66.

    Article  CAS  PubMed  Google Scholar 

  50. Keino-Masu K, Masu M, Hinck L, Leonardo ED, Chan SS, Culotti JG, et al. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell 1996;87:175–85.

    Article  CAS  PubMed  Google Scholar 

  51. Llambi F, Causeret F, Bloch-Gallego E, Mehlen P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. Embo J. 2001;20:2715–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Finci LI, Krüger N, Sun X, Zhang J, Chegkazi M, Wu Y, et al. The crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue. Neuron 2014;83:839–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Finger JH, Bronson RT, Harris B, Johnson K, Przyborski SA, Ackerman SL. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. J Neurosci. 2002;22:10346–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Forcet C, Stein E, Pays L, Corset V, Llambi F, Tessier-Lavigne M, et al. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Nature 2002;417:443–7.

    Article  CAS  PubMed  Google Scholar 

  55. Jarjour AA, Bull SJ, Almasieh M, Rajasekharan S, Baker KA, Mui J, et al. Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1. J Neurosci. 2008;28:11003–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rajasekharan S, Baker KA, Horn KE, Jarjour AA, Antel JP, Kennedy TE. Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA. Development 2009;136:415–26.

    Article  CAS  PubMed  Google Scholar 

  57. Mehlen P, Mazelin L. The dependence receptors DCC and UNC5H as a link between neuronal guidance and survival. Biol Cell. 2003;95:425–36.

    Article  CAS  PubMed  Google Scholar 

  58. Furne C, Rama N, Corset V, Chédotal A, Mehlen P. Netrin-1 is a survival factor during commissural neuron navigation. Proc Natl Acad Sci. 2008;105:14465–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen J, Du H, Zhang Y, Chen H, Zheng M, Lin P, et al. Netrin-1 Prevents Rat Primary Cortical Neurons from Apoptosis via the DCC/ERK Pathway. Front Cell Neurosci. 2017;11:387.

  60. Liu L, Liu KJ, Cao JB, Yang J, Yu HL, He XX, et al. A Novel Netrin-1-Derived Peptide Enhances Protection against Neuronal Death and Mitigates of Intracerebral Hemorrhage in Mice. Int J Mol Sci. 2021;22:4829.

  61. Furne C, Corset V, Hérincs Z, Cahuzac N, Hueber A-O, Mehlen P. The dependence receptor DCC requires lipid raft localization for cell death signaling. Proc Natl Acad Sci USA. 2006;103:4128–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Castets M, Broutier L, Molin Y, Brevet M, Chazot G, Gadot N, et al. DCC constrains tumour progression via its dependence receptor activity. Nature 2011;482:534–7.

    Article  PubMed  Google Scholar 

  63. Broutier L, Creveaux M, Vial J, Tortereau A, Delcros JG, Chazot G, et al. Targeting netrin-1/DCC interaction in diffuse large B-cell and mantle cell lymphomas. EMBO Mol Med. 2016;8:96–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Boussouar A, Tortereau A, Manceau A, Paradisi A, Gadot N, Vial J, et al. Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression. Cancer Res. 2020;80:747–56.

    Article  CAS  PubMed  Google Scholar 

  65. Mehlen P, Bredesen DE. The dependence receptor hypothesis. Apoptosis 2004;9:37–49.

    Article  CAS  PubMed  Google Scholar 

  66. Wheeler MA, Clark IC, Tjon EC, Li Z, Zandee SEJ, Couturier CP, et al. MAFG-driven astrocytes promote CNS inflammation. Nature 2020;578:593–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Assis-Nascimento P, Umland O, Cepero ML, Liebl DJ. A flow cytometric approach to analyzing mature and progenitor endothelial cells following traumatic brain injury. J Neurosci Methods. 2016;263:57–67.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Kennedy TE, Serafini T, de la Torre JR, Tessier-Lavigne M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 1994;78:425–35.

    Article  CAS  PubMed  Google Scholar 

  69. Schmued L, Bowyer J, Cozart M, Heard D, Binienda Z, Paule M. Introducing Black-Gold II, a highly soluble gold phosphate complex with several unique advantages for the histochemical localization of myelin. Brain Res. 2008;1229:210–7.

    Article  CAS  PubMed  Google Scholar 

  70. Wood RL. Accelerated cognitive aging following severe traumatic brain injury: A review. Brain Inj. 2017;31:1270–8.

    Article  PubMed  Google Scholar 

  71. Wu D, Kumal JPP, Lu X, Li Y, Mao D, Tang X, et al. Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer’s-Like Pathology in the Hippocampus by Altering the Phenotype of Microglia in the APP/PS1 Mouse Model. Front Neurol. 2021;12:666430.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Klugmann M, Schwab MH, Pühlhofer A, Schneider A, Zimmermann F, Griffiths IR, et al. Assembly of CNS myelin in the absence of proteolipid protein. Neuron 1997;18:59–70.

    Article  CAS  PubMed  Google Scholar 

  73. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 1998;280:1610–3.

    Article  CAS  PubMed  Google Scholar 

  74. Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 2012;485:517–21.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Duncan GJ, Simkins TJ, Emery B. Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons. Front Cell Dev Biol. 2021;9:653101.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Harris JJ, Attwell D. The energetics of CNS white matter. J Neurosci. 2012;32:356–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rosko L, Smith VN, Yamazaki R, Huang JK. Oligodendrocyte Bioenergetics in Health and Disease. Neuroscientist 2019;25:334–43.

    Article  CAS  PubMed  Google Scholar 

  78. Royet A, Broutier L, Coissieux MM, Malleval C, Gadot N, Maillet D, et al. Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4. Oncotarget 2017;8:23750–9.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ricard J, Salinas J, Garcia L, Liebl DJ. EphrinB3 regulates cell proliferation and survival in adult neurogenesis. Mol Cell Neurosci. 2006;31:713–22.

    Article  CAS  PubMed  Google Scholar 

  80. Furne C, Ricard J, Cabrera JR, Pays L, Bethea JR, Mehlen P, et al. EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis. Biochim Biophys Acta. 2009;1793:231–8.

    Article  CAS  PubMed  Google Scholar 

  81. Manitt C, Colicos MA, Thompson KM, Rousselle E, Peterson AC, Kennedy TE. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord. J Neurosci. 2001;21:3911–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hérincs Z, Corset V, Cahuzac N, Furne C, Castellani V, Hueber AO, et al. DCC association with lipid rafts is required for netrin-1-mediated axon guidance. J Cell Sci. 2005;118:1687–92.

    Article  PubMed  Google Scholar 

  83. Goldman JS, Ashour MA, Magdesian MH, Tritsch NX, Harris SN, Christofi N, et al. Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly. J Neurosci. 2013;33:17278–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Horn KE, Glasgow SD, Gobert D, Bull SJ, Luk T, Girgis J, et al. DCC expression by neurons regulates synaptic plasticity in the adult brain. Cell Rep. 2013;3:173–85.

    Article  CAS  PubMed  Google Scholar 

  85. Fuss B, Mallon B, Phan T, Ohlemeyer C, Kirchhoff F, Nishiyama A, et al. Purification and analysis of in vivo-differentiated oligodendrocytes expressing the green fluorescent protein. Dev Biol. 2000;218:259–74.

    Article  CAS  PubMed  Google Scholar 

  86. James SL, Theadom A, Ellenbogen RG, Bannick MS, Montjoy-Venning W, Lucchesi LR, et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:56–87.

    Article  Google Scholar 

  87. Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 2015;161:1202–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd, et al. Comprehensive Integration of Single-Cell Data. Cell 2019;177:1888–902. e21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Dixon KJ, Mier J, Gajavelli S, Turbic A, Bullock R, Turnley AM, et al. EphrinB3 restricts endogenous neural stem cell migration after traumatic brain injury. Stem Cell Res. 2016;17:504–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Perez EJ, Cepero ML, Perez SU, Coyle JT, Sick TJ, Liebl DJ. EphB3 signaling propagates synaptic dysfunction in the traumatic injured brain. Neurobiol Dis. 2016;94:73–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Perez EJ, Tapanes SA, Loris ZB, Balu DT, Sick TJ, Coyle JT, et al. Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. J Clin Investig. 2017;127:3114–25.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Vazquez-Rosa E, Watson MR, Sahn JJ, Hodges TR, Schroeder RE, Cintron-Perez CJ, et al. Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. ACS Chem Neurosci. 2019;10:1595–602.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Maria L. Cepero, Maria M Quiala-Acosta, and Jose Mier for technical assistance and animal husbandry. Dr Oliver Umland was instrumental in the flow cytometry gating and analysis. We thank Drs Haritha Desu and Roberta Brambilla for reagents and guidance. Lastly, we thank Dr Pantelis Tsoulfas and Yan Shi for microscopy support. Graphical model was created in Biorender.com.

Funding

This work was supported by the Miami Project to Cure Paralysis, National Institute of Health/National Institute of Neurological Disorders and Stroke (NS098740, NS120028), Foundation Bettencourt (PM), ANR (PM) and ligue contre le cancer (PM), and the Lois Pope Life Foundation.

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PM, DJL, and YT conceived the study. PM provided technical and material support. MMD, YT, DA, DJL, and PM provided acquisition, analysis, interpretation of data, and statistical analysis. MMD and DJL drafted the paper. All authors read and approved the paper.

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Correspondence to Patrick Mehlen or Daniel J. Liebl.

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Animal procedures were approved by the University of Miami Animal Use and Care Committee. No human subjects were involved in this study.

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Díaz, M.M., Tsenkina, Y., Arizanovska, D. et al. DCC/netrin-1 regulates cell death in oligodendrocytes after brain injury. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01091-z

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