Association between Hippo signaling pathway and myelination process in the Multiple sclerosis

Document Type : Review article


1 Division of Genetics, Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran

2 Associate Professor, Division of Genetics, Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran


Multiple sclerosis is an autoimmune inflammatory disease that causes the destruction of myelin and axonal degeneration. Given that multiple sclerosis is one of the most common neurological diseases, especially in young people, this disease is one of the main public health concerns. Therefore, it is important to understand the molecular mechanisms involved in the development of MS. Many molecular mechanisms control the process of myelination in the nervous system, and any changes in these regulatory mechanisms lead to impaired myelination. Current therapies have focus on controling the immune mechanisms involved in the disease process and are therefore only effective in the early stages of the disease and have no effect on axonal remyelination. But, therapies that reinforce the remyelination process may delay or prevent disability. Some recent studies have investigated the role of key genes of the Hippo signaling pathway in the myelination process of myelinating glial cells. According to these studies, the activity of YAP1/TAZ and its negative regulation in the Hippo pathway via CRB3, a cellular polarization factor, regulates myelin sheath synthesis. Thus, dysregulation of these genes can play a major role in the pathogenesis of many diseases related to the nervous system. Because there is no comprehensive review of the relationship between the hippo signaling pathway and multiple sclerosis; in this study, in addition to a narrative review of MS and its predisposing factors, the Hippo pathway as a pathway implicated in the defect of the myelination process in MS was investigated.


  1. Marzullo A, Kocevar G, Stamile C, Durand-Dubief F, Terracina G, Calimeri F, et al. Classification of Multiple Sclerosis Clinical Profiles via Graph Convolutional Neural Networks. Frontiers in neuroscience. 2019;13:594.
  2. Golshani Z, Hojati Z, Sharifzadeh A, Shaygannejad V, Jafarinia M. Genetic Variation in Intergenic and Exonic miRNA Sequence and Risk of Multiple Sclerosis in the Isfahan Patients. Iranian Journal of Allergy, Asthma and Immunology. 2018;17(5):477-84.
  3. Kister I, Chamot E, Salter AR, Cutter GR, Bacon TE, Herbert J. Disability in multiple sclerosis: a reference for patients and clinicians. Neurology. 2013;80(11):1018-24.
  4. Zalc B. One hundred and fifty years ago Charcot reported multiple sclerosis as a new neurological disease. Brain. 2018;141(12):3482-8.
  5. Lubetzki C. 150 years since Charcot's lectures on multiple sclerosis. The Lancet Neurology. 2018;17(12):1041.
  6. Compston A, Coles A. Multiple sclerosis. Lancet (British edition). 2008;372(9648):1502-17.
  7. Kay M, Hojati Z, Dehghanian F. The molecular study of IFNβ pleiotropic roles in MS treatment. Iranian journal of neurology. 2013;12(4):149.
  8. Compston A, Coles A. Multiple sclerosis. Lancet (British edition). 2002;359(9313):1221-31.
  9. Zwibel HL. Contribution of impaired mobility and general symptoms to the burden of multiple sclerosis. Advances in therapy. 2009;26(12):1043-57.
  10. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Annals of neurology. 2007;61(4):288-99.
  11. Zurawski J, Glanz BI, Healy BC, Tauhid S, Khalid F, Chitnis T, et al. The impact of cervical spinal cord atrophy on quality of life in multiple sclerosis. Journal of the neurological sciences. 2019;403:38-43.
  12. Martin CL, Phillips BA, Kilpatrick T, Butzkueven H, Tubridy N, Mcdonald E, et al. Gait and balance impairment in early multiple sclerosis in the absence of clinical disability. Multiple Sclerosis Journal. 2006;12(5):620-8.
  13. Cruickshank TM, Reyes AR, Ziman MR. A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease. Medicine. 2015;94(4).
  14. Sebastião E, Hubbard E, Klaren R, Pilutti L, Motl R. Fitness and its association with fatigue in persons with multiple sclerosis. Scandinavian journal of medicine & science in sports. 2017;27(12):1776-84.
  15. Alrouji M, Manouchehrinia A, Gran B, Constantinescu CS. Effects of cigarette smoke on immunity, neuroinflammation and multiple sclerosis. Journal of neuroimmunology. 2019;329:24-34.
  16. Alfredsson L, Olsson T. Lifestyle and environmental factors in multiple sclerosis. Cold Spring Harbor perspectives in medicine. 2019;9(4):a028944.
  17. Thakolwiboon S, Karukote A, Avila M. Late Onset Multiple Sclerosis: Clinical and Radiographic Characteristics (P4. 2-075). AAN Enterprises; 2019.
  18. Ghasemi N, Razavi S, Nikzad E. Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. Cell Journal (Yakhteh). 2017;19(1):1.
  19. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-.
  20. Melcon MO, Correale J, Melcon CM. Is it time for a new global classification of multiple sclerosis? Journal of the neurological sciences. 2014;344(1-2):171-81.
  21. Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Revue neurologique. 2016;172(1):3-13.
  22. Azami M, YektaKooshali MH, Shohani M, Khorshidi A, Mahmudi L. Correction: Epidemiology of multiple sclerosis in Iran: A systematic review and meta-analysis. PloS one. 2019;14(7).
  23. Voskuhl RR, Sawalha AH, Itoh Y. Sex chromosome contributions to sex differences in multiple sclerosis susceptibility and progression. Multiple Sclerosis Journal. 2018;24(1):22-31.
  24. Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung HP. Immunopathogenesis and immunotherapy of multiple sclerosis. Nature clinical practice Neurology. 2006;2(4):201-11.
  25. Jiang J, Kelly KA. Phenotype and function of regulatory T cells in the genital tract. Current trends in immunology. 2011;12:89-94.
  26. Bianchini E, De Biasi S, Simone AM, Ferraro D, Sola P, Cossarizza A, et al. Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis. Immunology letters. 2017;183:1-7.
  27. Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Archivum immunologiae et therapiae experimentalis. 2015;63(6):435-49.
  28. van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis and rheumatism. 2011;63(1):73-83.
  29. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. 2018;154(2):204-19.
  30. Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (Review). Molecular medicine reports. 2016;13(4):3391-6.
  31. Elfeky M, Kamimura D, Arima Y, Murakami M, Steinman L. Targeting molecules involved in immune cell trafficking to the central nervous system for therapy in multiple sclerosis. Clinical and Experimental Neuroimmunology. 2017;8(3):183-91.
  32. Grigoriadis N, Van Pesch V. A basic overview of multiple sclerosis immunopathology. European journal of neurology. 2015;22:3-13.
  33. Dehghanian F, Kay M, Hojati Z. Interferon gamma versus beta-interferon in pathogenesis of multiple sclerosis: Battle of two interferons. Neuroinflammation: Elsevier; 2018. p. 429-48.
  34. Dolati S, Babaloo Z, Jadidi-Niaragh F, Ayromlou H, Sadreddini S, Yousefi M. Multiple sclerosis: Therapeutic applications of advancing drug delivery systems. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2017;86:343-53.
  35. Inglese M, Petracca M. Therapeutic strategies in multiple sclerosis: a focus on neuroprotection and repair and relevance to schizophrenia. Schizophrenia research. 2015;161(1):94-101.
  36. Koriem KMM. Multiple sclerosis: New insights and trends. Asian Pacific Journal of Tropical Biomedicine. 2016;6(5):429-40.
  37. Kallaur AP, Lopes J, Oliveira SR, Simao AN, Reiche EM, de Almeida ER, et al. Immune-Inflammatory and Oxidative and Nitrosative Stress Biomarkers of Depression Symptoms in Subjects with Multiple Sclerosis: Increased Peripheral Inflammation but Less Acute Neuroinflammation. Molecular neurobiology. 2016;53(8):5191-202.
  38. Bernitsas E. Pathophysiology and Imaging Diagnosis of Demyelinating Disorders. Multidisciplinary Digital Publishing Institute; 2018.
  39. Luo C, Jian C, Liao Y, Huang Q, Wu Y, Liu X, et al. The role of microglia in multiple sclerosis. Neuropsychiatric disease and treatment. 2017;13:1661-7.
  40. Hojati Z, Kay M, Dehghanian F. Mechanism of action of interferon Beta in treatment of multiple sclerosis. Multiple Sclerosis: Elsevier; 2016. p. 365-92.
  41. Backhaus I, Mannocci A, La Torre G, Liccardi A. Cigarette Smoking and Nicotine: Effects on Multiple Sclerosis. Neuroscience of Nicotine: Elsevier; 2019. p. 97-105.
  42. Hedström A, Olsson T, Alfredsson L. Smoking is a major preventable risk factor for multiple sclerosis. Multiple Sclerosis Journal. 2016;22(8):1021-6.
  43. Hedström A, Alfredsson L, Lundkvist Ryner M, Fogdell-Hahn A, Hillert J, Olsson T. Smokers run increased risk of developing anti-natalizumab antibodies. Multiple Sclerosis Journal. 2014;20(8):1081-5.
  44. Hedström AK, Ryner M, Fink K, Fogdell-Hahn A, Alfredsson L, Olsson T, et al. Smoking and risk of treatment-induced neutralizing antibodies to interferon β-1a. Multiple Sclerosis Journal. 2014;20(4):445-50.
  45. Downham C, Visser E, Vickers M, Counsell C. Season of infectious mononucleosis as a risk factor for multiple sclerosis: A UK primary care case-control study. Multiple sclerosis and related disorders. 2017;17:103-6.
  46. Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PloS one. 2010;5(9):e12496.
  47. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature Reviews Neurology. 2017;13(1):25.
  48. Hojati Z. Molecular genetic and epigenetic basis of multiple sclerosis. Multiple Sclerosis: Bench to Bedside: Springer; 2017. p. 65-90.
  49. Wekerle H. Nature, nurture, and microbes: The development of multiple sclerosis. Acta Neurologica Scandinavica. 2017;136:22-5.
  50. Steenhof M, Nielsen NM, Stenager E, Kyvik K, Möller S, Hertz JM. Distribution of disease courses in familial vs sporadic multiple sclerosis. Acta Neurologica Scandinavica. 2019;139(3):231-7.
  51. Hoppenbrouwers IA, Liu F, Aulchenko YS, Ebers GC, Oostra BA, van Duijn CM, et al. Maternal transmission of multiple sclerosis in a Dutch population. Archives of neurology. 2008;65(3):345-8.
  52. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214.
  53. Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nature genetics. 2013;45(11):1353.
  54. Moutsianas L, Jostins L, Beecham AH, Dilthey AT, Xifara DK, Ban M, et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nature genetics. 2015;47(10):1107.
  55. Dehghanian F, Hojati Z, Hosseinkhan N, Mousavian Z, Masoudi-Nejad A. Reconstruction of the genome-scale co-expression network for the Hippo signaling pathway in colorectal cancer. Computers in biology and medicine. 2018;99:76-84.
  56. Zheng Y, Pan D. The hippo signaling pathway in development and disease. Developmental cell. 2019;50(3):264-82.
  57. Dehghanian F, Azhir Z, Akbari A, Hojati Z. New Insights into the Roles of Yes-Associated Protein (YAP1) in Colorectal Cancer Development and Progression. Annals of Colorectal Research. (In Press).
  58. Ji X, Zhong G, Zhao B. Molecular mechanisms of the mammalian Hippo signaling pathway. Yi chuan= Hereditas. 2017;39(7):546-67.
  59. Dehghanian F, Hojati Z, Esmaeili F, Masoudi-Nejad A. Network-based expression analyses and experimental validations revealed high co-expression between Yap1 and stem cell markers compared to differentiated cells. Genomics. 2019;111(4):831-9.
  60. Mao X, Li P, Wang Y, Liang Z, Liu J, Li J, et al. CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells. Cell death & disease. 2018;8(1):e2546-e.
  61. Roignot J, Peng X, Mostov K. Polarity in mammalian epithelial morphogenesis. Cold Spring Harbor Perspectives in Biology. 2013;5(2):a013789.
  62. Masaki T. Polarization and myelination in myelinating glia. ISRN neurology. 2012;2012.
  63. Tricaud N. Myelinating Schwann cell polarity and mechanically-driven myelin sheath elongation. Frontiers in cellular neuroscience. 2018;11:414.
  64. Assémat E, Bazellières E, Pallesi-Pocachard E, Le Bivic A, Massey-Harroche D. Polarity complex proteins. Biochimica et Biophysica Acta (BBA)-Biomembranes. 2008;1778(3):614-30.
  65. Fernando RN, Cotter L, Perrin-Tricaud C, Berthelot J, Bartolami S, Pereira JA, et al. Optimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway. Nature communications. 2016;7:12186.
  66. Thaxton C, Bott M, Walker B, Sparrow NA, Lambert S, Fernandez-Valle C. Schwannomin/merlin promotes Schwann cell elongation and influences myelin segment length. Molecular and Cellular Neuroscience. 2011;47(1):1-9.
  67. Elbediwy A, Vincentā€Mistiaen ZI, Thompson BJ. YAP and TAZ in epithelial stem cells: a sensor for cell polarity, mechanical forces and tissue damage. BioEssays. 2016;38(7):644-53.
  68. Yimlamai D, Fowl BH, Camargo FD. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. Journal of hepatology. 2015;63(6):1491-501.
  69. Tricaud N. Myelinating Schwann Cell Polarity and Mechanically-Driven Myelin Sheath Elongation. Frontiers in Cellular Neuroscience. 2018;11(414).
  70. Devaux JJ, Faivre-Sarrailh C. Neuro-glial interactions at the nodes of Ranvier: implication in health and diseases. Frontiers in cellular neuroscience. 2013;7:196.
  71. Sherman DL, Fabrizi C, Gillespie CS, Brophy PJ. Specific disruption of a schwann cell dystrophin-related protein complex in a demyelinating neuropathy. Neuron. 2001;30(3):677-87.
  72. Heller BA, Ghidinelli M, Voelkl J, Einheber S, Smith R, Grund E, et al. Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system. J Cell Biol. 2014;204(7):1219-36.
  73. Hildebrand C, Mustafa G, Waxman S. Remodelling of internodes in regenerated rat sciatic nerve: electron microscopic observations. Journal of neurocytology. 1986;15(6):681-92.
  74. Gomez-Sanchez JA, Pilch KS, van der Lans M, Fazal SV, Benito C, Wagstaff LJ, et al. After nerve injury, lineage tracing shows that myelin and Remak Schwann cells elongate extensively and branch to form repair Schwann cells, which shorten radically on remyelination. Journal of Neuroscience. 2017;37(37):9086-99.
  75. Willison HJ, Jacobs BC, van Doorn PA. Guillain-barre syndrome. The Lancet. 2016;388(10045):717-27.
  76. Chen Y-h, Zhang H, Meng L-b, Tang X-y, Gong T, Yin J. Novel mutation in the periaxin gene causal to Charcot–Marie–Tooth disease type 4F. Journal of International Medical Research. 2019:0300060519862064.
  77. Nguyen Q, Lim KRQ, Yokota T. Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy. The application of clinical genetics. 2019;12:113.
  78. Liang X, Wang S, Zhang W, Yuan Y, Ding J, Chang X, et al. Peripheral nerve injury in LAMA2-related congenital muscular dystrophy patients. Zhonghua er ke za zhi= Chinese journal of pediatrics. 2017;55(2):95-9.
  79. Poitelon Y, Lopez-Anido C, Catignas K, Berti C, Palmisano M, Williamson C, et al. YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells. Nature neuroscience. 2016;19(7):879-87.
  80. Deng Y, Wu LMN, Bai S, Zhao C, Wang H, Wang J, et al. A reciprocal regulatory loop between TAZ/YAP and G-protein Gαs regulates Schwann cell proliferation and myelination. Nature communications. 2017;8(1):1-15.
  81. Grove M, Lee H, Zhao H, Son Y-J. Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury. eLife. 2020;9:e50138.