EGR2 and SOX10-mediated initiation of Schwann cell myelination (Homo sapiens)

From WikiPathways

Revision as of 11:55, 2 November 2020 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
9, 13, 45, 69, 70, 9722, 35, 61, 62, 8368, 89, 9410, 63, 67, 68, 75...8, 35, 56, 62, 64...16, 46, 48, 57, 62...10, 28, 63, 67, 68, 75...9, 11, 19, 65, 66, 917, 32, 35, 8318, 23, 46, 52, 851, 5, 34, 82, 9623, 31, 46, 48, 52...3, 9, 14, 15, 17...4, 12, 33, 40, 51...7, 32, 35, 39, 59...18, 47, 72, 8121, 42, 57, 58, 854, 12, 31, 33, 40...46, 57, 858, 35, 56, 62, 839, 11, 19, 24, 25, 31...6, 12, 49, 62, 87...9, 19, 20, 29, 41...2, 6, 12, 43, 49...22, 30, 35, 50, 53...21, 42, 57, 581, 5, 82, 96endoplasmic reticulum lumennucleoplasmcytosolADGRG6-CTF PMP22 Gene NAB1 GJB1 genePOU3F1 CYP51A1 gene SREBF2 dimerPOU3F1 geneSREBF2(1-484) HMGCRgene:EGR2:SREBF2dimerPRXL-PRXHMGCR geneSMARCA4 SREBF2(1-484) NAB1 EGR2gene:POU3F1:POU3F2:SOX10DAG1(654-895) L-PRX DystroglycanPOU3F1 gene:SOX10dimer:HDAC2:SMARCA4PMP22YAP1 PRX geneEGR2 SCD5gene:EGR2:SREBF2dimerDRP2 GJB1 gene ADGRG6DAG1(30-653) EGR2 HMGCRYAP1 MPZ gene HDAC2 POU3F1LAMC1 MAG gene:EGR2:SOX10L-PRXdimer:DRP2:Dystroglycan:Laminin-211SOX10 SMARCA4ADGRG6-CTF DRP2 MBP gene:EGR2:SOX10DAG1(654-895) GJB11gene:SOX10:EGR2:NAB1,2WWTR1 DAG1(30-653) L-PRX:DRP2:dystroglycan:laminin-211:UTRNMAG geneLAMC1 EGR2 NAB2 HMGCR gene CYP51A1EGR2 EGR2 SOX10 SREBF2(1-484) PMP22 GeneSOX10 MBP geneLAMA2 LAMA2 PMP22gene:EGR2:SOX10:TEAD1:WWTR1,YAP1EGR2 HDAC2DAG1(30-653) LAMB1 LAMB1 UTRN POU3F2 DRP2SOX10 EGR2 ADGRG6-CTF:ADGRG6-NTFMBP gene SREBF2(1-484) ADGRG6-NTF MPZ geneGPR98ADGRG6-CTF:ADGRG6-NTFTEAD1 SMARCA4 PRX gene:EGR2:SOX10SOX10 PRX gene WWTR1 DRP2 LAMA2 MBPEGR2 geneEGR2 SOX10 EGR2 gene EGR2 Laminin-211POU3F2L-PRX MAGL-PRX TEAD1:WWTR1,YAP1NAB1,2SOX10 LAMB1 SCD5 gene POU3F1 gene UTRNNAB2 DAG1(654-895) CYP51A1 geneSCD5TEAD1 LAMC1 CYP51A1gene:EGR2:SREBF2dimerMAG gene SCD5 geneSOX10MPZMPZgene:EGR2:SOX10:SMARCA4L-PRX dimer:DRP2EGR2ADGRG6-NTF SOX10 37


Description

Schwann cells are glial cells of the peripheral nervous system that ensheath the peripheral nerves within a compacted lipid-rich myelin structure that is required for optimal transduction of nerve signals in motor and sensory nerves. Schwann cells develop from the neural crest in a differentiation process driven by factors derived from the Schwann cell itself, from the adjacent neuron or from the extracellular matrix (reviewed in Jessen and Mirsky, 2005). Upon peripheral nerve injury, mature Schwann cells can form repair cells that allow peripheral nerve regeneration through myelin phagocytosis and remyelination of the peripheral nerve. This process in some ways recapitulates the maturation of immature Schwann cells during development (reviewed in Jessen and Mirsky, 2016). Mature, fully myelinated Schwann cells exhibit longitudinal and radial polarization. The axon-distal abaxonal membrane interacts with elements of the basal lamina through integrins and lamins and in this way resembles the basolateral domain of polarized epithelial cells. In contrast, the axon-proximal adaxonal membrane resembles the apical domain of an epithelial cell, and is enriched with adhesion molecules and receptors that mediate interaction with ligands from the axon (reviewed in Salzer, 2015).
Schwann cells express a number of Schwann-cell specific proteins, including components of the myelin sheath such as myelin basic protein (MBP) and myelin protein zero (MPZ). In addition, Schwann cells have high lipid content relative to other membranes, and are enriched in galactosphingolipids, cholesterol and saturated long chain fatty acids (reviewed in Garbay et al, 2000). This protein and lipid profile is driven by a Schwann cell myelination transcriptional program controlled by master regulators SOX10, POU3F1 and EGR2, among others (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9619665
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Rothfels, Karen

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Moriguchi T, Haraguchi K, Ueda N, Okada M, Furuya T, Akiyama T.; ''DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites.''; PubMed Europe PMC Scholia
  2. Jones EA, Brewer MH, Srinivasan R, Krueger C, Sun G, Charney KN, Keles S, Antonellis A, Svaren J.; ''Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22.''; PubMed Europe PMC Scholia
  3. Jaegle M, Mandemakers W, Broos L, Zwart R, Karis A, Visser P, Grosveld F, Meijer D.; ''The POU factor Oct-6 and Schwann cell differentiation.''; PubMed Europe PMC Scholia
  4. Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, Lupski JR.; ''Periaxin mutations cause recessive Dejerine-Sottas neuropathy.''; PubMed Europe PMC Scholia
  5. Langenhan T, Aust G, Hamann J.; ''Sticky signaling--adhesion class G protein-coupled receptors take the stage.''; PubMed Europe PMC Scholia
  6. Maier M, Berger P, Nave KA, Suter U.; ''Identification of the regulatory region of the peripheral myelin protein 22 (PMP22) gene that directs temporal and spatial expression in development and regeneration of peripheral nerves.''; PubMed Europe PMC Scholia
  7. Wang J, Yu L, Schmidt RE, Su C, Huang X, Gould K, Cao G.; ''Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates.''; PubMed Europe PMC Scholia
  8. Strömstedt M, Rozman D, Waterman MR.; ''The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols.''; PubMed Europe PMC Scholia
  9. Svaren J, Meijer D.; ''The molecular machinery of myelin gene transcription in Schwann cells.''; PubMed Europe PMC Scholia
  10. Sherman DL, Wu LM, Grove M, Gillespie CS, Brophy PJ.; ''Drp2 and periaxin form Cajal bands with dystroglycan but have distinct roles in Schwann cell growth.''; PubMed Europe PMC Scholia
  11. Chen Y, Wang H, Yoon SO, Xu X, Hottiger MO, Svaren J, Nave KA, Kim HA, Olson EN, Lu QR.; ''HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination.''; PubMed Europe PMC Scholia
  12. Srinivasan R, Sun G, Keles S, Jones EA, Jang SW, Krueger C, Moran JJ, Svaren J.; ''Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve.''; PubMed Europe PMC Scholia
  13. Salzer JL.; ''Schwann cell myelination.''; PubMed Europe PMC Scholia
  14. Newbern J, Birchmeier C.; ''Nrg1/ErbB signaling networks in Schwann cell development and myelination.''; PubMed Europe PMC Scholia
  15. Lee MM, Badache A, DeVries GH.; ''Phosphorylation of CREB in axon-induced Schwann cell proliferation.''; PubMed Europe PMC Scholia
  16. McKerracher L, Rosen KM.; ''MAG, myelin and overcoming growth inhibition in the CNS.''; PubMed Europe PMC Scholia
  17. Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS.; ''A G protein-coupled receptor is essential for Schwann cells to initiate myelination.''; PubMed Europe PMC Scholia
  18. Lopez-Anido C, Sun G, Koenning M, Srinivasan R, Hung HA, Emery B, Keles S, Svaren J.; ''Differential Sox10 genomic occupancy in myelinating glia.''; PubMed Europe PMC Scholia
  19. Weider M, Küspert M, Bischof M, Vogl MR, Hornig J, Loy K, Kosian T, Müller J, Hillgärtner S, Tamm ER, Metzger D, Metzger D, Wegner M.; ''Chromatin-remodeling factor Brg1 is required for Schwann cell differentiation and myelination.''; PubMed Europe PMC Scholia
  20. Mandemakers W, Zwart R, Jaegle M, Walbeehm E, Visser P, Grosveld F, Meijer D.; ''A distal Schwann cell-specific enhancer mediates axonal regulation of the Oct-6 transcription factor during peripheral nerve development and regeneration.''; PubMed Europe PMC Scholia
  21. LeBlanc SE, Jang SW, Ward RM, Wrabetz L, Svaren J.; ''Direct regulation of myelin protein zero expression by the Egr2 transactivator.''; PubMed Europe PMC Scholia
  22. Pai JT, Guryev O, Brown MS, Goldstein JL.; ''Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins.''; PubMed Europe PMC Scholia
  23. Denarier E, Forghani R, Farhadi HF, Dib S, Dionne N, Friedman HC, Lepage P, Hudson TJ, Drouin R, Peterson A.; ''Functional organization of a Schwann cell enhancer.''; PubMed Europe PMC Scholia
  24. Bahrami S, Drabløs F.; ''Gene regulation in the immediate-early response process.''; PubMed Europe PMC Scholia
  25. O'Donovan KJ, Tourtellotte WG, Millbrandt J, Baraban JM.; ''The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience.''; PubMed Europe PMC Scholia
  26. Morgan L, Jessen KR, Mirsky R.; ''The effects of cAMP on differentiation of cultured Schwann cells: progression from an early phenotype (04+) to a myelin phenotype (P0+, GFAP-, N-CAM-, NGF-receptor-) depends on growth inhibition.''; PubMed Europe PMC Scholia
  27. Monk KR, Oshima K, Jörs S, Heller S, Talbot WS.; ''Gpr126 is essential for peripheral nerve development and myelination in mammals.''; PubMed Europe PMC Scholia
  28. Ervasti JM, Campbell KP.; ''A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin.''; PubMed Europe PMC Scholia
  29. Ghazvini M, Mandemakers W, Jaegle M, Piirsoo M, Driegen S, Koutsourakis M, Smit X, Grosveld F, Meijer D.; ''A cell type-specific allele of the POU gene Oct-6 reveals Schwann cell autonomous function in nerve development and regeneration.''; PubMed Europe PMC Scholia
  30. Jurevics H, Bouldin TW, Toews AD, Morell P.; ''Regenerating sciatic nerve does not utilize circulating cholesterol.''; PubMed Europe PMC Scholia
  31. Topilko P, Schneider-Maunoury S, Levi G, Baron-Van Evercooren A, Chennoufi AB, Seitanidou T, Babinet C, Charnay P.; ''Krox-20 controls myelination in the peripheral nervous system.''; PubMed Europe PMC Scholia
  32. Zhang S, Yang Y, Shi Y.; ''Characterization of human SCD2, an oligomeric desaturase with improved stability and enzyme activity by cross-linking in intact cells.''; PubMed Europe PMC Scholia
  33. Han H, Kursula P.; ''Periaxin and AHNAK nucleoprotein 2 form intertwined homodimers through domain swapping.''; PubMed Europe PMC Scholia
  34. Lin HH, Chang GW, Davies JQ, Stacey M, Harris J, Gordon S.; ''Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif.''; PubMed Europe PMC Scholia
  35. Leblanc SE, Srinivasan R, Ferri C, Mager GM, Gillian-Daniel AL, Wrabetz L, Svaren J.; ''Regulation of cholesterol/lipid biosynthetic genes by Egr2/Krox20 during peripheral nerve myelination.''; PubMed Europe PMC Scholia
  36. Ghislain J, Desmarquet-Trin-Dinh C, Jaegle M, Meijer D, Charnay P, Frain M.; ''Characterisation of cis-acting sequences reveals a biphasic, axon-dependent regulation of Krox20 during Schwann cell development.''; PubMed Europe PMC Scholia
  37. Vachon PH, Loechel F, Xu H, Wewer UM, Engvall E.; ''Merosin and laminin in myogenesis; specific requirement for merosin in myotube stability and survival.''; PubMed Europe PMC Scholia
  38. Zhao FQ.; ''Octamer-binding transcription factors: genomics and functions.''; PubMed Europe PMC Scholia
  39. Tabor DE, Kim JB, Spiegelman BM, Edwards PA.; ''Identification of conserved cis-elements and transcription factors required for sterol-regulated transcription of stearoyl-CoA desaturase 1 and 2.''; PubMed Europe PMC Scholia
  40. Guilbot A, Williams A, Ravisé N, Verny C, Brice A, Sherman DL, Brophy PJ, LeGuern E, Delague V, Bareil C, Mégarbané A, Claustres M.; ''A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease.''; PubMed Europe PMC Scholia
  41. Jagalur NB, Ghazvini M, Mandemakers W, Driegen S, Maas A, Jones EA, Jaegle M, Grosveld F, Svaren J, Meijer D.; ''Functional dissection of the Oct6 Schwann cell enhancer reveals an essential role for dimeric Sox10 binding.''; PubMed Europe PMC Scholia
  42. Peirano RI, Goerich DE, Riethmacher D, Wegner M.; ''Protein zero gene expression is regulated by the glial transcription factor Sox10.''; PubMed Europe PMC Scholia
  43. van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M.; ''PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies.''; PubMed Europe PMC Scholia
  44. Herdegen T, Leah JD.; ''Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins.''; PubMed Europe PMC Scholia
  45. Stolt CC, Wegner M.; ''Schwann cells and their transcriptional network: Evolution of key regulators of peripheral myelination.''; PubMed Europe PMC Scholia
  46. Jang SW, LeBlanc SE, Roopra A, Wrabetz L, Svaren J.; ''In vivo detection of Egr2 binding to target genes during peripheral nerve myelination.''; PubMed Europe PMC Scholia
  47. Le N, Nagarajan R, Wang JY, Svaren J, LaPash C, Araki T, Schmidt RE, Milbrandt J.; ''Nab proteins are essential for peripheral nervous system myelination.''; PubMed Europe PMC Scholia
  48. Le N, Nagarajan R, Wang JY, Araki T, Schmidt RE, Milbrandt J.; ''Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.''; PubMed Europe PMC Scholia
  49. Maier M, Castagner F, Berger P, Suter U.; ''Distinct elements of the peripheral myelin protein 22 (PMP22) promoter regulate expression in Schwann cells and sensory neurons.''; PubMed Europe PMC Scholia
  50. Vallett SM, Sanchez HB, Rosenfeld JM, Osborne TF.; ''A direct role for sterol regulatory element binding protein in activation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene.''; PubMed Europe PMC Scholia
  51. Topilko P, Levi G, Merlo G, Mantero S, Desmarquet C, Mancardi G, Charnay P.; ''Differential regulation of the zinc finger genes Krox-20 and Krox-24 (Egr-1) suggests antagonistic roles in Schwann cells.''; PubMed Europe PMC Scholia
  52. Forghani R, Garofalo L, Foran DR, Farhadi HF, Lepage P, Hudson TJ, Tretjakoff I, Valera P, Peterson A.; ''A distal upstream enhancer from the myelin basic protein gene regulates expression in myelin-forming schwann cells.''; PubMed Europe PMC Scholia
  53. Saher G, Simons M.; ''Cholesterol and myelin biogenesis.''; PubMed Europe PMC Scholia
  54. Jurevics HA, Morell P.; ''Sources of cholesterol for kidney and nerve during development.''; PubMed Europe PMC Scholia
  55. Pagel JI, Deindl E.; ''Early growth response 1--a transcription factor in the crossfire of signal transduction cascades.''; PubMed Europe PMC Scholia
  56. Strushkevich N, Usanov SA, Park HW.; ''Structural basis of human CYP51 inhibition by antifungal azoles.''; PubMed Europe PMC Scholia
  57. LeBlanc SE, Ward RM, Svaren J.; ''Neuropathy-associated Egr2 mutants disrupt cooperative activation of myelin protein zero by Egr2 and Sox10.''; PubMed Europe PMC Scholia
  58. Marathe HG, Mehta G, Zhang X, Datar I, Mehrotra A, Yeung KC, de la Serna IL.; ''SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.''; PubMed Europe PMC Scholia
  59. Tabor DE, Kim JB, Spiegelman BM, Edwards PA.; ''Transcriptional activation of the stearoyl-CoA desaturase 2 gene by sterol regulatory element-binding protein/adipocyte determination and differentiation factor 1.''; PubMed Europe PMC Scholia
  60. Pérez-Cadahía B, Drobic B, Davie JR.; ''Activation and function of immediate-early genes in the nervous system.''; PubMed Europe PMC Scholia
  61. Verheijen MH, Chrast R, Burrola P, Lemke G.; ''Local regulation of fat metabolism in peripheral nerves.''; PubMed Europe PMC Scholia
  62. Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J.; ''EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression.''; PubMed Europe PMC Scholia
  63. Yamada H, Shimizu T, Tanaka T, Campbell KP, Matsumura K.; ''Dystroglycan is a binding protein of laminin and merosin in peripheral nerve.''; PubMed Europe PMC Scholia
  64. Halder SK, Fink M, Waterman MR, Rozman D.; ''A cAMP-responsive element binding site is essential for sterol regulation of the human lanosterol 14alpha-demethylase gene (CYP51).''; PubMed Europe PMC Scholia
  65. Ghislain J, Charnay P.; ''Control of myelination in Schwann cells: a Krox20 cis-regulatory element integrates Oct6, Brn2 and Sox10 activities.''; PubMed Europe PMC Scholia
  66. Reiprich S, Kriesch J, Schreiner S, Wegner M.; ''Activation of Krox20 gene expression by Sox10 in myelinating Schwann cells.''; PubMed Europe PMC Scholia
  67. Court FA, Hewitt JE, Davies K, Patton BL, Uncini A, Wrabetz L, Feltri ML.; ''A laminin-2, dystroglycan, utrophin axis is required for compartmentalization and elongation of myelin segments.''; PubMed Europe PMC Scholia
  68. Sherman DL, Fabrizi C, Gillespie CS, Brophy PJ.; ''Specific disruption of a schwann cell dystrophin-related protein complex in a demyelinating neuropathy.''; PubMed Europe PMC Scholia
  69. Jessen KR, Mirsky R.; ''The repair Schwann cell and its function in regenerating nerves.''; PubMed Europe PMC Scholia
  70. Garbay B, Heape AM, Sargueil F, Cassagne C.; ''Myelin synthesis in the peripheral nervous system.''; PubMed Europe PMC Scholia
  71. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL.; ''Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.''; PubMed Europe PMC Scholia
  72. Bondurand N, Girard M, Pingault V, Lemort N, Dubourg O, Goossens M.; ''Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10.''; PubMed Europe PMC Scholia
  73. Parkinson DB, Dickinson S, Bhaskaran A, Kinsella MT, Brophy PJ, Sherman DL, Sharghi-Namini S, Duran Alonso MB, Mirsky R, Jessen KR.; ''Regulation of the myelin gene periaxin provides evidence for Krox-20-independent myelin-related signalling in Schwann cells.''; PubMed Europe PMC Scholia
  74. Schnaar RL, Lopez PH.; ''Myelin-associated glycoprotein and its axonal receptors.''; PubMed Europe PMC Scholia
  75. Yamada H, Chiba A, Endo T, Kobata A, Anderson LV, Hori H, Fukuta-Ohi H, Kanazawa I, Campbell KP, Shimizu T, Matsumura K.; ''Characterization of dp6troglycan-laminin interaction in peripheral nerve.''; PubMed Europe PMC Scholia
  76. Monuki ES, Kuhn R, Weinmaster G, Trapp BD, Lemke G.; ''Expression and activity of the POU transcription factor SCIP.''; PubMed Europe PMC Scholia
  77. Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR.; ''Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation.''; PubMed Europe PMC Scholia
  78. Imamura M, Araishi K, Noguchi S, Ozawa E.; ''A sarcoglycan-dystroglycan complex anchors Dp116 and utrophin in the peripheral nervous system.''; PubMed Europe PMC Scholia
  79. Ryu EJ, Wang JY, Le N, Baloh RH, Gustin JA, Schmidt RE, Milbrandt J.; ''Misexpression of Pou3f1 results in peripheral nerve hypomyelination and axonal loss.''; PubMed Europe PMC Scholia
  80. Court FA, Sherman DL, Pratt T, Garry EM, Ribchester RR, Cottrell DF, Fleetwood-Walker SM, Brophy PJ.; ''Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves.''; PubMed Europe PMC Scholia
  81. Neuhaus IM, Bone L, Wang S, Ionasescu V, Werner R.; ''The human connexin32 gene is transcribed from two tissue-specific promoters.''; PubMed Europe PMC Scholia
  82. Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT.; ''A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.''; PubMed Europe PMC Scholia
  83. Jang SW, Srinivasan R, Jones EA, Sun G, Keles S, Krueger C, Chang LW, Nagarajan R, Svaren J.; ''Locus-wide identification of Egr2/Krox20 regulatory targets in myelin genes.''; PubMed Europe PMC Scholia
  84. Schreiner S, Cossais F, Fischer K, Scholz S, Bösl MR, Holtmann B, Sendtner M, Wegner M.; ''Hypomorphic Sox10 alleles reveal novel protein functions and unravel developmental differences in glial lineages.''; PubMed Europe PMC Scholia
  85. Jones EA, Jang SW, Mager GM, Chang LW, Srinivasan R, Gokey NG, Ward RM, Nagarajan R, Svaren J.; ''Interactions of Sox10 and Egr2 in myelin gene regulation.''; PubMed Europe PMC Scholia
  86. Jaegle M, Ghazvini M, Mandemakers W, Piirsoo M, Driegen S, Levavasseur F, Raghoenath S, Grosveld F, Meijer D.; ''The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.''; PubMed Europe PMC Scholia
  87. Lopez-Anido C, Poitelon Y, Gopinath C, Moran JJ, Ma KH, Law WD, Antonellis A, Feltri ML, Svaren J.; ''Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development.''; PubMed Europe PMC Scholia
  88. Jones EA, Lopez-Anido C, Srinivasan R, Krueger C, Chang LW, Nagarajan R, Svaren J.; ''Regulation of the PMP22 gene through an intronic enhancer.''; PubMed Europe PMC Scholia
  89. Masaki T, Matsumura K.; ''Biological role of dystroglycan in Schwann cell function and its implications in peripheral nervous system diseases.''; PubMed Europe PMC Scholia
  90. Kim M, Wende H, Walcher J, Kühnemund J, Cheret C, Kempa S, McShane E, Selbach M, Lewin GR, Birchmeier C.; ''Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells.''; PubMed Europe PMC Scholia
  91. Jacob C, Christen CN, Pereira JA, Somandin C, Baggiolini A, Lötscher P, Ozçelik M, Tricaud N, Meijer D, Yamaguchi T, Matthias P, Suter U.; ''HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells.''; PubMed Europe PMC Scholia
  92. Shin D, Lin ST, Fu YH, Ptácek LJ.; ''Very large G protein-coupled receptor 1 regulates myelin-associated glycoprotein via Gαs/Gαq-mediated protein kinases A/C.''; PubMed Europe PMC Scholia
  93. Castelnovo LF, Bonalume V, Melfi S, Ballabio M, Colleoni D, Magnaghi V.; ''Schwann cell development, maturation and regeneration: a focus on classic and emerging intracellular signaling pathways.''; PubMed Europe PMC Scholia
  94. Wrabetz L, Feltri ML.; ''Do Schwann cells stop, DR(o)P2, and roll?''; PubMed Europe PMC Scholia
  95. Camargo N, Smit AB, Verheijen MH.; ''SREBPs: SREBP function in glia-neuron interactions.''; PubMed Europe PMC Scholia
  96. Mehta P, Piao X.; ''Adhesion G-protein coupled receptors and extracellular matrix proteins: Roles in myelination and glial cell development.''; PubMed Europe PMC Scholia
  97. Jessen KR, Mirsky R.; ''The origin and development of glial cells in peripheral nerves.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
115036view16:57, 25 January 2021ReactomeTeamReactome version 75
113480view11:55, 2 November 2020ReactomeTeamReactome version 74
112832view18:35, 9 October 2020DeSlOntology Term : 'regulatory pathway pertinent to the brain' added !
112831view18:35, 9 October 2020DeSlOntology Term : 'Schwann cell' added !
112830view18:34, 9 October 2020DeSlOntology Term : 'myelinating Schwann cell' added !
112777view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADGRG6-CTF ProteinQ86SQ4 (Uniprot-TrEMBL)
ADGRG6-CTF:ADGRG6-NTFComplexR-HSA-9614270 (Reactome)
ADGRG6-CTF:ADGRG6-NTFComplexR-HSA-9614274 (Reactome)
ADGRG6-NTF ProteinQ86SQ4 (Uniprot-TrEMBL)
ADGRG6ProteinQ86SQ4 (Uniprot-TrEMBL)
CYP51A1

gene:EGR2:SREBF2

dimer
ComplexR-HSA-9621347 (Reactome)
CYP51A1 gene ProteinENSG00000001630 (Ensembl)
CYP51A1 geneGeneProductENSG00000001630 (Ensembl)
CYP51A1ProteinQ16850 (Uniprot-TrEMBL)
DAG1(30-653) ProteinQ14118 (Uniprot-TrEMBL)
DAG1(654-895) ProteinQ14118 (Uniprot-TrEMBL)
DRP2 ProteinQ13474 (Uniprot-TrEMBL)
DRP2ProteinQ13474 (Uniprot-TrEMBL)
DystroglycanComplexR-HSA-2328140 (Reactome)
EGR2 gene:POU3F1:POU3F2:SOX10ComplexR-HSA-9613761 (Reactome)
EGR2 ProteinP11161 (Uniprot-TrEMBL)
EGR2 gene ProteinENSG00000122877 (Ensembl)
EGR2 geneGeneProductENSG00000122877 (Ensembl)
EGR2ProteinP11161 (Uniprot-TrEMBL)
GJB1 gene ProteinENSG00000169562 (Ensembl)
GJB1 geneGeneProductENSG00000169562 (Ensembl)
GJB11 gene:SOX10:EGR2:NAB1,2ComplexR-HSA-9618726 (Reactome)
GPR98ProteinQ8WXG9 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
HDAC2ProteinQ92769 (Uniprot-TrEMBL)
HMGCR

gene:EGR2:SREBF2

dimer
ComplexR-HSA-9621351 (Reactome)
HMGCR gene ProteinENSG00000113161 (Ensembl)
HMGCR geneGeneProductENSG00000113161 (Ensembl)
HMGCRProteinP04035 (Uniprot-TrEMBL)
L-PRX dimer:DRP2:Dystroglycan:Laminin-211ComplexR-HSA-9619606 (Reactome)
L-PRX ProteinQ9BXM0-1 (Uniprot-TrEMBL)
L-PRX dimer:DRP2ComplexR-HSA-9619603 (Reactome)
L-PRX:DRP2:dystroglycan:laminin-211:UTRNComplexR-HSA-9619612 (Reactome)
L-PRXProteinQ9BXM0-1 (Uniprot-TrEMBL)
LAMA2 ProteinP24043 (Uniprot-TrEMBL)
LAMB1 ProteinP07942 (Uniprot-TrEMBL)
LAMC1 ProteinP11047 (Uniprot-TrEMBL)
Laminin-211ComplexR-HSA-216003 (Reactome)
MAG gene ProteinENSG00000105695 (Ensembl)
MAG gene:EGR2:SOX10ComplexR-HSA-9616114 (Reactome)
MAG geneGeneProductENSG00000105695 (Ensembl)
MAGProteinP20916 (Uniprot-TrEMBL)
MBP gene ProteinENSG00000105695 (Ensembl)
MBP gene:EGR2:SOX10ComplexR-HSA-9615629 (Reactome)
MBP geneGeneProductENSG00000105695 (Ensembl)
MBPProteinP02686 (Uniprot-TrEMBL)
MPZ gene:EGR2:SOX10:SMARCA4ComplexR-HSA-9614793 (Reactome)
MPZ gene ProteinENSG00000158887 (Ensembl)
MPZ geneGeneProductENSG00000158887 (Ensembl)
MPZProteinP25189 (Uniprot-TrEMBL)
NAB1 ProteinQ13506 (Uniprot-TrEMBL)
NAB1,2ComplexR-HSA-9612546 (Reactome)
NAB2 ProteinQ15742 (Uniprot-TrEMBL)
PMP22 gene:EGR2:SOX10:TEAD1:WWTR1,YAP1ComplexR-HSA-9618555 (Reactome)
PMP22 Gene ProteinENSG00000109099 (Ensembl)
PMP22 GeneGeneProductENSG00000109099 (Ensembl)
PMP22ProteinQ01453 (Uniprot-TrEMBL)
POU3F1 ProteinQ03052 (Uniprot-TrEMBL)
POU3F1 gene ProteinENSG00000185668 (Ensembl)
POU3F1 gene:SOX10 dimer:HDAC2:SMARCA4ComplexR-HSA-9613641 (Reactome)
POU3F1 geneGeneProductENSG00000185668 (Ensembl)
POU3F1ProteinQ03052 (Uniprot-TrEMBL)
POU3F2 ProteinP20265 (Uniprot-TrEMBL)
POU3F2ProteinP20265 (Uniprot-TrEMBL)
PRX gene ProteinENSG00000105227 (Ensembl)
PRX gene:EGR2:SOX10ComplexR-HSA-9619633 (Reactome)
PRX geneGeneProductENSG00000105227 (Ensembl)
PRXProteinQ9BXM0 (Uniprot-TrEMBL)
SCD5

gene:EGR2:SREBF2

dimer
ComplexR-HSA-9621358 (Reactome)
SCD5 gene ProteinENSG00000145284 (Ensembl)
SCD5 geneGeneProductENSG00000145284 (Ensembl)
SCD5ProteinQ86SK9 (Uniprot-TrEMBL)
SMARCA4 ProteinP51532 (Uniprot-TrEMBL)
SMARCA4ProteinP51532 (Uniprot-TrEMBL)
SOX10 ProteinP56693 (Uniprot-TrEMBL)
SOX10ProteinP56693 (Uniprot-TrEMBL)
SREBF2 dimerComplexR-HSA-2317550 (Reactome)
SREBF2(1-484) ProteinQ12772 (Uniprot-TrEMBL)
TEAD1 ProteinP28347 (Uniprot-TrEMBL)
TEAD1:WWTR1,YAP1ComplexR-HSA-9618556 (Reactome)
UTRN ProteinP46939 (Uniprot-TrEMBL)
UTRNProteinP46939 (Uniprot-TrEMBL)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
YAP1 ProteinP46937 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADGRG6-CTF:ADGRG6-NTFArrowR-HSA-9613644 (Reactome)
ADGRG6-CTF:ADGRG6-NTFArrowR-HSA-9614271 (Reactome)
ADGRG6-CTF:ADGRG6-NTFArrowR-HSA-9614273 (Reactome)
ADGRG6-CTF:ADGRG6-NTFR-HSA-9614273 (Reactome)
ADGRG6R-HSA-9614271 (Reactome)
ADGRG6mim-catalysisR-HSA-9614271 (Reactome)
ArrowR-HSA-9614778 (Reactome)
CYP51A1

gene:EGR2:SREBF2

dimer
ArrowR-HSA-9621404 (Reactome)
CYP51A1

gene:EGR2:SREBF2

dimer
ArrowR-HSA-9621406 (Reactome)
CYP51A1 geneR-HSA-9621404 (Reactome)
CYP51A1 geneR-HSA-9621406 (Reactome)
CYP51A1ArrowR-HSA-9621404 (Reactome)
DRP2R-HSA-9619669 (Reactome)
DystroglycanR-HSA-9619666 (Reactome)
EGR2 gene:POU3F1:POU3F2:SOX10ArrowR-HSA-9613760 (Reactome)
EGR2 gene:POU3F1:POU3F2:SOX10ArrowR-HSA-9613768 (Reactome)
EGR2 geneR-HSA-9613760 (Reactome)
EGR2 geneR-HSA-9613768 (Reactome)
EGR2ArrowR-HSA-9613760 (Reactome)
EGR2R-HSA-9614790 (Reactome)
EGR2R-HSA-9615638 (Reactome)
EGR2R-HSA-9616116 (Reactome)
EGR2R-HSA-9618559 (Reactome)
EGR2R-HSA-9618725 (Reactome)
EGR2R-HSA-9619657 (Reactome)
EGR2R-HSA-9621400 (Reactome)
EGR2R-HSA-9621406 (Reactome)
EGR2R-HSA-9621411 (Reactome)
GJB1 geneR-HSA-9618725 (Reactome)
GJB11 gene:SOX10:EGR2:NAB1,2ArrowR-HSA-9618725 (Reactome)
GPR98ArrowR-HSA-9614778 (Reactome)
HDAC2R-HSA-9613648 (Reactome)
HMGCR

gene:EGR2:SREBF2

dimer
ArrowR-HSA-9621410 (Reactome)
HMGCR

gene:EGR2:SREBF2

dimer
ArrowR-HSA-9621411 (Reactome)
HMGCR geneR-HSA-9621410 (Reactome)
HMGCR geneR-HSA-9621411 (Reactome)
HMGCRArrowR-HSA-9621410 (Reactome)
L-PRX dimer:DRP2:Dystroglycan:Laminin-211ArrowR-HSA-9619666 (Reactome)
L-PRX dimer:DRP2:Dystroglycan:Laminin-211R-HSA-9619668 (Reactome)
L-PRX dimer:DRP2ArrowR-HSA-9619669 (Reactome)
L-PRX dimer:DRP2R-HSA-9619666 (Reactome)
L-PRX:DRP2:dystroglycan:laminin-211:UTRNArrowR-HSA-9619668 (Reactome)
L-PRXR-HSA-9619669 (Reactome)
Laminin-211R-HSA-9619666 (Reactome)
MAG gene:EGR2:SOX10ArrowR-HSA-9616116 (Reactome)
MAG geneR-HSA-9614778 (Reactome)
MAG geneR-HSA-9616116 (Reactome)
MAGArrowR-HSA-9614778 (Reactome)
MBP gene:EGR2:SOX10ArrowR-HSA-9614773 (Reactome)
MBP gene:EGR2:SOX10ArrowR-HSA-9615638 (Reactome)
MBP geneR-HSA-9614773 (Reactome)
MBP geneR-HSA-9615638 (Reactome)
MBPArrowR-HSA-9614773 (Reactome)
MPZ gene:EGR2:SOX10:SMARCA4ArrowR-HSA-9614787 (Reactome)
MPZ gene:EGR2:SOX10:SMARCA4ArrowR-HSA-9614790 (Reactome)
MPZ geneR-HSA-9614787 (Reactome)
MPZ geneR-HSA-9614790 (Reactome)
MPZArrowR-HSA-9614787 (Reactome)
NAB1,2R-HSA-9618725 (Reactome)
PMP22 gene:EGR2:SOX10:TEAD1:WWTR1,YAP1ArrowR-HSA-9615626 (Reactome)
PMP22 gene:EGR2:SOX10:TEAD1:WWTR1,YAP1ArrowR-HSA-9618559 (Reactome)
PMP22 GeneR-HSA-9615626 (Reactome)
PMP22 GeneR-HSA-9618559 (Reactome)
PMP22ArrowR-HSA-9615626 (Reactome)
POU3F1 gene:SOX10 dimer:HDAC2:SMARCA4ArrowR-HSA-9613644 (Reactome)
POU3F1 gene:SOX10 dimer:HDAC2:SMARCA4ArrowR-HSA-9613648 (Reactome)
POU3F1 geneR-HSA-9613644 (Reactome)
POU3F1 geneR-HSA-9613648 (Reactome)
POU3F1ArrowR-HSA-9613644 (Reactome)
POU3F1R-HSA-9613768 (Reactome)
POU3F2R-HSA-9613768 (Reactome)
PRX gene:EGR2:SOX10ArrowR-HSA-9619657 (Reactome)
PRX gene:EGR2:SOX10ArrowR-HSA-9619667 (Reactome)
PRX geneR-HSA-9619657 (Reactome)
PRX geneR-HSA-9619667 (Reactome)
PRXArrowR-HSA-9619667 (Reactome)
R-HSA-9613644 (Reactome) POU3F1, also known as OCT6, is a transcription factor involved in early embyrogenesis and neuronal developement, particularly the myelination of Schwann cells in the peripheral nervous system (Monuki et al, 1990; Jaegle et al, 1996; Ryu et al, 2007; reviewed in Zhao, 2013; Svaren and Meijer, 2008). Expression of POU3F1 in Schwann cells is transient, and peaks at the promyelination stage, and loss of POUF3F1 causese a delay in myelination (Jaegle et al, 2003; Jaegle et al, 1996).
Expression of POU3F1 is driven in part by the Schwann Cell Enhancer (SCE), which is bound by a dimer of SOX10, a key regulator of Schwann cell development (Jagalur et al, 2011). POU3F1 expression is also regulated by the adhesion GPCR ADGRG6 (also known as GPR126). Expression of POU3F1 and EGR2 is lost in grp126 mutant, which arrest at a promyelinating stage (Monk et al, 2009; Monk et al, 2011). ADGRG6 elevates cAMP levels through G alpha s G proteins, and may control POU3F1 expression through the cAMP-PKA-CREB pathway (Morgan et al, 1991; Lee et al, 1999; Mandemakers et al, 2000; Monk et al, 2009; Monk et al, 2011; Mogha et al, 2013; reviewed in Svaren and Meijer). CREB phosphorylation may also be regulated by the NRG1-ERBB2:ERBB3 pathway (reviewedi n Newbern and Birchmeier,2010).
After induction, POU3F1, POU3F2 (also known as OCT7) and SOX10 work together in a feedforward mechanism to activate expression of EGR2, which ultimately promotes expression of genes encoding myelin components, such as myelin protein zero (MPZ) and myelin basic protein (MBP) (Ghislain and Charnay, 2006; Le Blanc et al, 2006; Le Blanc et al, 2007; Marathe et al, 2013; reviewed in Stolt and Wegner, 2016; Svaren and Meijer, 2008)
R-HSA-9613648 (Reactome) SOX10 binds as a dimer to the Schwann cell enhancer (SCE) element in the promoter of the POU3F1 gene (Jagalur et al, 2011; Schreiner et al, 2007; Ghazvini et al, 2002; Mandemakers et al, 2000). SOX10 mediates recruitment of chromatin remodeling complexes and histone deacetlyases, including HDAC2 and SMARCA4, promoting transcriptional activation of POU3F1 (Jacob et al, 2011; Weider et al, 2012).
POU3F1 protein (also known as OCT6) is required in conjunction with EGR2 to ensheath axonal neurons of the peripheral nervous system with myelin (reviewed in Svaren and Meijer, 2008). The myelination program is initiated by extracellular axonal signals such as NRG, Neuregulin1, Notch ligands and neurotrophins and is transmitted to the nucleus, ultimately controling expression of myelin-related genes, including myelin protein zero (MPZ) and myelin basic protein (MBP), among others. After synthesis, OCT6 acts in conjunction with SOX10 and EGR2, a master regulator of myelination, to drive expression of these genes (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016).
R-HSA-9613760 (Reactome) EGR2 (also known as KROX20) is a member of the Early Growth Response (EGR) gene family encoding sequence-specific Cys2-His2 DNA binding transcription factors. The EGR family are immediate early genes (IEGs) whose expression is rapidly upregulated in response to a number of external stimuli to control activation of genes involved in stress response and differentiation (reviewed in Pagel and Deindl, 2001; Bahrami and Drabløs, 2016). Roles for EGR proteins are well established in the nervous system, with EGR target genes contributing to synaptic plasticity, long-term potentiation, peripheral nerve myelination and NGF-induced neurite outgrowth (reviewed in Perez-Cadahia et al, 2011; Herdegen and Leah, 1998; O'Donovan et al, 1999)
In addition to its other roles, EGR2 is a critical regulator of myelination by Schwann cells in the peripheral nervous system (reviewed in Svaren and Meijer, 2008). Consistent with this, Schwann cells are blocked at the promyelinating stage in EGR2 knockouts in mice (Topilko et al, 1994). Expression of EGR2 during the myelination process is controlled by a myelinating Schwann cell enhancer (MSE) 35 kb downstream of the gene (Ghislain et al, 2002). The MSE is bound by SOX10, POU3F1 and POU3F2 (Ghislain and Charnay, 2006; Reiprich et al, 2010). SOX10 in turn recruits SMARCA4, HDAC1 and HDAC2 to play overlapping but non-redundant roles in activating EGR2 expression (Jacob et al, 2011; Chen et al, 2011; Weider et al, 2012).
R-HSA-9613768 (Reactome) During the process of peripheral nerve myelination, EGR2 expression is controlled by a feedforward transcriptional program initiated by SOX10 and maintained by POU3F2, PU3F1 and EGR2 itself (reviewed in Svaren and Meijer, 2008). Expression of EGR2 during the myelination process is controlled by a myelinating Schwann cell enhancer (MSE) 35 kb downstream of the gene (Ghislain et al, 2002). The MSE is bound by SOX10, POU3F1 and POU3F2 (Ghislain and Charnay, 2006; Reiprich et al, 2010). SOX10 in turn recruits SMARCA4, HDAC1 and HDAC2 to play overlapping but non-redundant roles in activating EGR2 expression (Jacob et al, 2011; Chen et al, 2011; Weider et al, 2012).
R-HSA-9614271 (Reactome) ADGRG6, also known as GPR126, is a member of the adhesion class of G-protein coupled receptors (aGPCRs). aGPCRs are characterized by a 7 transmembrane-spanning domain that couples to G-protein signaling and an extracellular N-terminal extension that mediates cell-cell or cell-matrix adhesion (reviewed in Langenhan et al, 2013). Like most aGPCRs, ADGRG6 is subject to autocatalytic processing during maturation, yielding a C-terminal fragment containing the 7-TM region, and an N-terminal fragment containing the extracellular region. Cleavage occurs at the conserved GPCR proteolytic site (GPS), part of the larger GPCR autoproteolysis-inducing (GAIN) domain (Moriguchi et al, 2004; Arac et al, 2012). As with other aGPCRs, these two domains remain associated in a heterodimer at the plasma membrane where they mediate signaling and cell adhesion (Moriguchi et al 2004; Arac et al, 2012; Lin et al, 2004; reviewed in Langenhan et al, 2013; Mehta et al, 2017).
R-HSA-9614273 (Reactome) Mature ADGRG6 is expressed at the plasma membrane as a non-covalently associated heterodimer of the N- and C terminal fragments (Moriguchi et al, 2004; Arac et al, 2012; reviewed in Langenhan et al, 2013; Mehta et al, 2017). In addition to cleavage at the GPS site, ADGRG6 may additionally be cleaved in the trans-Golgi network by a furin-like protease at an S2 site upstream of the GPS site. This cleavage yields a soluble N-terminal-most subfragment that may have roles in non cell autonomous signaling or contribute to regulation of ADGRG6 activation/inactivation (Moriguchi et al, 2004; reviewed in Langenhan et al, 2013).
R-HSA-9614773 (Reactome) Myelin basic protein (MBP) is a key component of the myelin sheath synthesized by Schwan cells in the peripheral nervous system (Garbay et al, 2000). MBP expression is regulated by EGR2, which binds to both to an upstream enhancer and to sites within the first intron of the MBP gene (Forgahni et al, 2001; Denarier et al, 2005; Jang et al, 2006). Consistent with this, MBP expression is decreased in EGR2 knockout mice (Topilko et al, 1994, Le et al, 2005). Sequence analysis suggests that, as is the case for MPZ, SOX10 may act in conjunction with EGR2 to regulate MBP expression (Jones et al, 2006).
R-HSA-9614778 (Reactome) Myelin associated glycoprotein (MAG) is a low abundant component of the myelin sheath and is synthesized by oligodendrocytes and Schwann cells in the central and peripheral nervous system, respectively. MAG is also an adhesion molecule that binds to gangliosides and glycoproteins such as RTN4R and RTN4RL2 to mediate interaction between myelinating cells and neurons, and additionally functions after injury in the CNS to inhibit axon regeneration through the RHO A signaling pathway (reviewed in Schnarr and Lopez, 2009; Mehta et al, 2017; McKerracher and Rosen, 2015).
MAG expression is regulated in part by the binding of EGR2 and SOX10 to elements in the second intron of the gene (LeBlanc et al, 2007; Jang et al, 2006; Jones et al, 2007). Consistent with this, MAG expression is abrogated in EGR2-depleted mice and stimulated by ectopic EGR2 expression (Le et al, 2005; Nagarajan et al, 2001). At the protein level, MAG stability is postively regulated by the adhesion GPCR protein GPR98 (also known as VLGR1). GPR98 signals through G proteins, PKA and PKA to limit MAG ubiquitination and subsequent degradation, although the mechanism remains to be elucidated (Shin et al, 2013; reviewed in Mehta and Piao, 2017).
R-HSA-9614787 (Reactome) MPZ is the most abundant component of the myelin sheath that surrounds axons of the peripheral nervous system. Expression of MPZ is dependent on axonal signals that stimulate the binding of transcriptional regulators EGR2 and SOX10 to response elements in intron 1, where they recruit SMARCA4 to the gene (Le Blanc et al, 2006; Le Blanc et al, 2007; Jones et al, 2007; Marathe et al, 2013). SOX10 additionally binds to elements in the promoter of MPZ, where it regulates both basal and upregulated MPZ expression (Peirano et al, 2000).
R-HSA-9614790 (Reactome) MPZ is a key component of the myelin sheath that surrounds axons of the peripheral nervous system. Expression of MPZ is dependent on binding of transcriptional regulators EGR2 and SOX10 to response elements in intron 1, where they recruit SMARCA4 to the gene (Le Blanc et al, 2006; Le Blanc et al, 2007; Marathe et al, 2013). SOX10 additionally binds to elements in the promoter of MPZ (Peirano et al, 2000).
R-HSA-9615626 (Reactome) The PMP22 gene encodes a peripheral myelin protein that is a component of the myelin sheath surrounding axons in the peripheral nervous system (reviewed in Garbay et al, 2000; Svaren and Meijer, 2008). Point mutations and duplications in the PMP22 gene cause the most prevalent form of the demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease, while deletions lead to Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (reviewed in van Passsen et al, 2014). PMP22 expression is controlled by a number of upstream and intronic enhancer elements that are bound by EGR2 and SOX10, master regulators of peripheral nerve myelination (Nagarajan et al, 2001; Maier et al, 2002; Maier et al, 2003; Jones et al, 2011; Jones et al, 2012; Srinivasan et al, 2012). In addition, PMP22 enhancers contain binding sites for the Hippo pathway transcription factor TEAD1, and TEAD1 and co-activators WWTR1 (also known as TAZ) and YAP1 are required for PMP22 expression (Lopez-Anido et al, 2016).
R-HSA-9615638 (Reactome) Myelin basic protein (MBP) is a key component in the myelin sheath that coats axons of the peripheral nervous system. MBP expression is regulated by EGR2 binding to sites in an enhancer that lies ~9kb upstream of the transcriptional start site, as well as to a binding site in the first intron (Forgahni et al, 2001; Denarier et al, 2005; Jang et al, 2006; Jones et al, 2007). Based on conservation of binding sites, SOX10 is predicted to also contribute to MBP expression during myelination (Jones et al, 2007), and this is substantiated by ChIP seq analysis and Sox10 knockdown studies in mouse (Arido-Lopez et al, 2015).
R-HSA-9616116 (Reactome) EGR2 and SOX10 bind to elements in the MAG gene to promote expression during myelination in the peripheral and central nervous system (Jones et al, 2007; Jang et al, 2006; LeBlanc et al, 2007).
R-HSA-9618559 (Reactome) PMP22 gene expression is regulated during peripheral nerve myelination by the binding of EGR2 and SOX10 to upstream and intronic enhancer elements (Nagarajan et al, 2001; Maier et al, 2002; Maier et al, 2003; Jones et al, 2011; Srinivasan et al, 2012). Hippo signaling also influences PMP22 expression during peripheral never myelination by modulating the binding of the TEAD1, WWTR1 (also known as TAZ) and YAP1 to cognate sites in the PMP22 gene (Lopez-Anido et al, 2016; reviewed in Castelnovo et al, 2017).
R-HSA-9618725 (Reactome) GJB1 expression is regulated by two alternate promoters in a tissue specific manner. In Schwann cells, expression is driven by the P2 promoter and depends on binding by SOX10, EGR2 and NAB1 or NAB2 (Neuhaus et al, 1996; Bondurand et al, 2001; Le et al, 2005; Lopez-Arido et al, 2015).
R-HSA-9619657 (Reactome) Periaxin (PRX) is a scaffolding protein that is part of a dystrophin:dystroglycan complex required for maintenance of the myelin sheath in Schwann cells. PRX homodimers interact with DRP2 to form a complex with dystroglycan at the basal lamina, anchoring the complex in the plasma membrane (Sherman et al, 2001; Han and Kursala, 2014). Mutations in PRX are associated with severe demyelinating peripheral neuropathies (Boerkoel et al, 2001; Guilbot et al, 2001).
Expression of PRX initiates earlier than EGR2 during peripheral nerve cell myelination, indicating an EGR2-independent mechanism early during myelination (Parkinson et al, 2003). Candidate regulators of this early expression include SOX10 and EGR1, which is expressed in embryonic Schwann cells and with EGR2 at postnatal day 1 (Topilko et al, 1997). Sustained, upregulated expression of PRX during myelination depends on the binding of EGR2 and SOX10 to a binding site within the first intron, 4.5 kb from the transcription start site (Jones et al, 2007; Srinivasan et al, 2012). Consistent with this, expression of PRX is decreased in EGR2 null mice (Nagarajan et al, 2001; Boerkoel et al, 2001).
R-HSA-9619666 (Reactome) The DRP2:L-PRX complex interacts with dystroglycan in the plasma membrane as part of the dystrophin glycoprotein complex (DGC) (Sherman et al, 2001; Court et al 2009; Sherman et al, 2012). DGC complexes have structural and signaling roles and provide a connection between the abaxonal Schwann cell plasma membrane and the adjacent basal lamina through interaction with laminin complexes, including laminin-211 (Ervasti et al, 1993; Yamada et al, 1994; Yamada et al, 1996; Imamura et al, 2000; reviewed in Wrabetz and Feltri, 2001; Masaki and Matsumura, 2010).
R-HSA-9619667 (Reactome) Periaxin (PRX) is a scaffolding protein that is part of a dystrophin:dystroglycan complex required for maintenance of the myelin sheath in Schwann cells. PRX homodimers interact with DRP2 to form a complex with dystroglycan at the basal lamina, anchoring the complex in the plasma membrane (Sherman et al, 2001; Han and Kursala, 2014). Mutations in PRX are associated with severe demyelinating peripheral neuropathies (Boerkoel et al, 2001; Guilbot et al, 2001).
Expression of PRX initiates earlier than EGR2 during peripheral nerve cell myelination, indicating an EGR2-independent mechanism early during myelination (Parkinson et al, 2003). Candidate regulators of this early expression include SOX10 and EGR1, which is expressed in embryonic Schwann cells and with EGR2 at postnatal day 1 (Topilko et al, 1997). Sustained, upregulated expression of PRX during myelination depends on the binding of EGR2 and SOX10 to a binding site within the first intron, 4.5 kb from the transcription start site (Jones et al, 2007; Srinivasan et al, 2012). Consistent with this, expression of PRX is decreased in EGR2 null mice (Nagarajan et al, 2001; Boerkoel et al, 2001).
R-HSA-9619668 (Reactome) Based on studies in mouse cells, L-PRX co-immunoprecipitates in a complex that includes DRP2, alpha- and beta-dystroglycan and dystrophin family utrophin (UTRN) (Sherman et al, 2001; reviewed in Wrabetz and Feltri, 2001; Masaki and Matsumura, 2010). Because UTRN does not interact directly with L-PRX, it is possible they are recruited indirectly through as part of alternate DGC complexes with varied dystrophin family members. This model remains to be validated, however (Sherman et al, 2001).
R-HSA-9619669 (Reactome) L-Periaxin (L-PRX) is a membrane protein that is expressed in Schwann cells of the peripheral nervous system where it acts as a key component of the dystrophin glycoprotein complex (DGC). PRX is required for the proper localization of a dystrophin-related protein DRP2 to sites of apposition between the Schwann cell plasma membrane and the abaxonal surface of the myelin sheath (Sherman et al, 2001; Sherman et al, 2012; Court et al, 2004; Court et al, 2009; reviewed in Masaki and Matsumura, 2010). The spectrin repeats of DRP2 and the basic subdomains of L-PRZ mediate direct interaction between the two proteins. S-PRZ, an alternate isofom that lacks the basic subdomains of L-PRZ, does not interact with DRP2 (Sherman et al, 2001). The complex of L-PRX and DRP2 also interact with other dystrophin-related proteins such as utrophin, as well as dystroglycan and components of the basal lumina, such as laminin-211 (Yamada et al, 1994; Yamada et al, 1996; Sherman et al, 2001).
PRZ and DRP2 have partially overlapping but distinct roles in myelin sheath formation. Both are required for the formation of appositions between the plasma membrane and the myelin sheath and for the formation of Cajal bodies. PRX also contributes to normal Schwann cell elongation and regulation of internode space along the axon, which is required for nerve conduction, while DRP2 is dispensable for these activities (Court et al, 2009; Sherman et al, 2012;)
R-HSA-9621399 (Reactome) Stearoyl-CoA desaturase 5 (SCD5, also known as acyl-CoA desaturase 4 or SCD2) is a ER-membrane protein involved in the desturation of fatty acyl-CoA substrates (Wang et al, 2005; Zhang et al, 2005). SCD5 gene expression is upregulated in an SREBF2- and EGR2-dependent manner during Schwann cell myelination (Tabor et al, 1998; Tabor et al, 1999; Horton et al, 2003; LeBlanc et al, 2004; Jang et al, 2010).
R-HSA-9621400 (Reactome) SCD5 expression is upregulated during Schwann cell myelination in an EGR2- and SREBF2 dependent manner (LeBlanc et all, 2005; Jang et al, 2010). SCD5 encodes a stearyl-CoA desaturase involved in long chain fatty acid biosynthesis (Wang et al, 2005; Zhang et al, 2005).
R-HSA-9621404 (Reactome) CYP51A1 encodes lanosterol 14 alpha-demethylase, an enzyme involved in steroid biosynthesis (Stroemstedt et al, 1996; Strushkevich et al, 2010). CYP51A1 is upregulated during Schwann cell myelination in an EGR2- and SREBF2-dependent manner, and sites for these factors have been identified in the upstream promoter region (Nagarajan et al, 2001; Halder et al, 2002; LeBlanc et al, 2005; Jang et al, 2010).
R-HSA-9621406 (Reactome) CYP51A1 encodes lanosterol 14 alpha-demethylase, a protein involved in steroid biosynthetic pathways (Stromstedt et al, 1996; Strushkevich et al, 2010). Consistent with its expression during Schwann cell myelination, expression is synergistically activated by EGR2 and SREBF2 acting through cognate sites in the promoter (Nagarajan et al, 2001; Halder et al, 2002; LeBlanc et al, 2005; Jang et al, 2010).
R-HSA-9621410 (Reactome) Cholesterol is highly enriched in the Schwann cell membrane and it plays an essential role in the maturation of MPZ, a key protein component of the compact myelin sheath (Saher and Simons, 2010). The cholesterol of the myelin sheath is synthesized within the Schwann cells, rather than being absorbed from the blood (Jurevics and Morell, 1994; Jurevics et al, 1998). Consistent with this, a number of genes involved in the cholesterol biosynthesis pathway are upregulated during the myelination program, including HMG synthase and HMG coenzyme-A reductase (HMGCR) (Nagarjan et al, 2001; Verheijen et al, 2003; Le Blanc et al, 2005; Jang et al, 2010; Kim et al, 2016; reviewed in Camargo et al, 2009). Myelin-specific expression of HMGCR depends on binding of sterol response binding factor 2 (SREBF2) to its cognate SRE site in the HMGCR promoter (Vallett et al, 1996; Pai et al, 1998; LeBlanc et al, 2005). SREBF2-dependent expression of HMGCR is increased with co-expression of EGR2, suggesting that the transcription factors synergistically activate expression (LeBlanc et al, 2005).
R-HSA-9621411 (Reactome) HMG coenzyme A reductase catalyzes a rate-limiting step in cholesterol biosynthesis and is expressed in a SREBF2- and EGR2-dependent manner during Schwann cell myelination. Cognate binding sites for both SREBF2 and EGR2 have been identified in the promoter of HMGCR, and the transcription factors act synergistically to promote transcription (Pai et al, 1998; Nagarajan et al, 2001; Verheijen et al, 2003; LeBlanc et al, 2005; Jang et al, 2010).
SCD5

gene:EGR2:SREBF2

dimer
ArrowR-HSA-9621399 (Reactome)
SCD5

gene:EGR2:SREBF2

dimer
ArrowR-HSA-9621400 (Reactome)
SCD5 geneR-HSA-9621399 (Reactome)
SCD5 geneR-HSA-9621400 (Reactome)
SCD5ArrowR-HSA-9621399 (Reactome)
SMARCA4R-HSA-9613648 (Reactome)
SMARCA4R-HSA-9614790 (Reactome)
SOX10R-HSA-9613648 (Reactome)
SOX10R-HSA-9613768 (Reactome)
SOX10R-HSA-9614790 (Reactome)
SOX10R-HSA-9615638 (Reactome)
SOX10R-HSA-9616116 (Reactome)
SOX10R-HSA-9618559 (Reactome)
SOX10R-HSA-9618725 (Reactome)
SOX10R-HSA-9619657 (Reactome)
SREBF2 dimerR-HSA-9621400 (Reactome)
SREBF2 dimerR-HSA-9621406 (Reactome)
SREBF2 dimerR-HSA-9621411 (Reactome)
TEAD1:WWTR1,YAP1R-HSA-9618559 (Reactome)
UTRNR-HSA-9619668 (Reactome)
Personal tools