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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Mar 15, 1998; 101(6): 1292–1299.
PMCID: PMC508683

Neurological disturbances, premature lethality, and central myelination deficiency in transgenic mice overexpressing the homeo domain transcription factor Oct-6.

Abstract

Pit, Oct, Unc (POU) homeo domain transcription factors have been implicated in various developmental processes, including cell division, differentiation, specification, and survival of specific cell types. Although expression of the transcription factor Oct-6 in oligodendroglia is confined to the promyelin stage and is downregulated at the myelin stage of development, the effect of Oct-6 overexpression on oligodendrocyte development has not been established. Here we show that transgenic animals overexpressing Oct-6 at late oligodendrocyte development develop a severe neurologic syndrome characterized by action tremors, recurrent seizures, and premature death. Axons in the central nervous system of Oct-6 transgenics were hypomyelinated, hypermyelinated, or dysmyelinated, and ultrastructural analyses suggested that myelin formation was premature. The vulnerability of developing oligodendroglia to Oct-6 deregulation provides evidence that the POU factor may play a direct role in myelin disease pathogenesis in the mammalian CNS.

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Selected References

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  • Pfeiffer SE, Warrington AE, Bansal R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 1993 Jun;3(6):191–197. [PubMed]
  • Remahl S, Hilderbrand C. Relation between axons and oligodendroglial cells during initial myelination. I. The glial unit. J Neurocytol. 1990 Jun;19(3):313–328. [PubMed]
  • Butt AM, Ransom BR. Morphology of astrocytes and oligodendrocytes during development in the intact rat optic nerve. J Comp Neurol. 1993 Dec 1;338(1):141–158. [PubMed]
  • Mirsky R, Jessen KR. Schwann cell development, differentiation and myelination. Curr Opin Neurobiol. 1996 Feb;6(1):89–96. [PubMed]
  • Ruvkun G, Finney M. Regulation of transcription and cell identity by POU domain proteins. Cell. 1991 Feb 8;64(3):475–478. [PubMed]
  • Rosenfeld MG. POU-domain transcription factors: pou-er-ful developmental regulators. Genes Dev. 1991 Jun;5(6):897–907. [PubMed]
  • Schöler HR. Octamania: the POU factors in murine development. Trends Genet. 1991 Oct;7(10):323–329. [PubMed]
  • Herr W, Cleary MA. The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev. 1995 Jul 15;9(14):1679–1693. [PubMed]
  • Monuki ES, Weinmaster G, Kuhn R, Lemke G. SCIP: a glial POU domain gene regulated by cyclic AMP. Neuron. 1989 Dec;3(6):783–793. [PubMed]
  • Suzuki N, Rohdewohld H, Neuman T, Gruss P, Schöler HR. Oct-6: a POU transcription factor expressed in embryonal stem cells and in the developing brain. EMBO J. 1990 Nov;9(11):3723–3732. [PMC free article] [PubMed]
  • He X, Gerrero R, Simmons DM, Park RE, Lin CJ, Swanson LW, Rosenfeld MG. Tst-1, a member of the POU domain gene family, binds the promoter of the gene encoding the cell surface adhesion molecule P0. Mol Cell Biol. 1991 Mar;11(3):1739–1744. [PMC free article] [PubMed]
  • Hara Y, Rovescalli AC, Kim Y, Nirenberg M. Structure and evolution of four POU domain genes expressed in mouse brain. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3280–3284. [PMC free article] [PubMed]
  • Spaniol P, Bornmann C, Hauptmann G, Gerster T. Class III POU genes of zebrafish are predominantly expressed in the central nervous system. Nucleic Acids Res. 1996 Dec 15;24(24):4874–4881. [PMC free article] [PubMed]
  • Rohdewohld H, Gruss P. The gene for the POU domain transcription factor Oct-6 maps to the distal end of mouse chromosome 4. Mamm Genome. 1992;3(2):119–121. [PubMed]
  • Avraham KB, Cho BC, Gilbert D, Fujii H, Okamoto K, Shimazaki T, Ito T, Shoji H, Wakamatsu Y, Kondoh H, et al. Murine chromosomal location of four class III POU transcription factors. Genomics. 1993 Oct;18(1):131–133. [PubMed]
  • Abdel-Rahman B, Fiddler M, Rappolee D, Pergament E. Expression of transcription regulating genes in human preimplantation embryos. Hum Reprod. 1995 Oct;10(10):2787–2792. [PubMed]
  • Zwart R, Broos L, Grosveld G, Meijer D. The restricted expression pattern of the POU factor Oct-6 during early development of the mouse nervous system. Mech Dev. 1996 Feb;54(2):185–194. [PubMed]
  • Frantz GD, Bohner AP, Akers RM, McConnell SK. Regulation of the POU domain gene SCIP during cerebral cortical development. J Neurosci. 1994 Feb;14(2):472–485. [PubMed]
  • Alvarez-Bolado G, Rosenfeld MG, Swanson LW. Model of forebrain regionalization based on spatiotemporal patterns of POU-III homeobox gene expression, birthdates, and morphological features. J Comp Neurol. 1995 May 1;355(2):237–295. [PubMed]
  • Collarini EJ, Kuhn R, Marshall CJ, Monuki ES, Lemke G, Richardson WD. Down-regulation of the POU transcription factor SCIP is an early event in oligodendrocyte differentiation in vitro. Development. 1992 Sep;116(1):193–200. [PubMed]
  • Faus I, Hsu HJ, Fuchs E. Oct-6: a regulator of keratinocyte gene expression in stratified squamous epithelia. Mol Cell Biol. 1994 May;14(5):3263–3275. [PMC free article] [PubMed]
  • Meijer D, Graus A, Grosveld G. Mapping the transactivation domain of the Oct-6 POU transcription factor. Nucleic Acids Res. 1992 May 11;20(9):2241–2247. [PMC free article] [PubMed]
  • Monuki ES, Kuhn R, Lemke G. Repression of the myelin P0 gene by the POU transcription factor SCIP. Mech Dev. 1993 Jul;42(1-2):15–32. [PubMed]
  • Renner K, Leger H, Wegner M. The POU domain protein Tst-1 and papovaviral large tumor antigen function synergistically to stimulate glia-specific gene expression of JC virus. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6433–6437. [PMC free article] [PubMed]
  • Leger H, Sock E, Renner K, Grummt F, Wegner M. Functional interaction between the POU domain protein Tst-1/Oct-6 and the high-mobility-group protein HMG-I/Y. Mol Cell Biol. 1995 Jul;15(7):3738–3747. [PMC free article] [PubMed]
  • Wegner M, Drolet DW, Rosenfeld MG. POU-domain proteins: structure and function of developmental regulators. Curr Opin Cell Biol. 1993 Jun;5(3):488–498. [PubMed]
  • Scherer SS, Wang DY, Kuhn R, Lemke G, Wrabetz L, Kamholz J. Axons regulate Schwann cell expression of the POU transcription factor SCIP. J Neurosci. 1994 Apr;14(4):1930–1942. [PubMed]
  • Blanchard AD, Sinanan A, Parmantier E, Zwart R, Broos L, Meijer D, Meier C, Jessen KR, Mirsky R. Oct-6 (SCIP/Tst-1) is expressed in Schwann cell precursors, embryonic Schwann cells, and postnatal myelinating Schwann cells: comparison with Oct-1, Krox-20, and Pax-3. J Neurosci Res. 1996 Dec 1;46(5):630–640. [PubMed]
  • Bermingham JR, Jr, Scherer SS, O'Connell S, Arroyo E, Kalla KA, Powell FL, Rosenfeld MG. Tst-1/Oct-6/SCIP regulates a unique step in peripheral myelination and is required for normal respiration. Genes Dev. 1996 Jul 15;10(14):1751–1762. [PubMed]
  • 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. Science. 1996 Jul 26;273(5274):507–510. [PubMed]
  • Bögler O, Entwistle A, Kuhn R, Monuki E, Lemke G, Noble M. Single cell analysis of the expression of a nuclear protein, SCIP, by fluorescent immunohistochemistry visualized with confocal microscopy. Histochem J. 1993 Oct;25(10):746–761. [PubMed]
  • Jensen NA, Smith GM, Shine HD, Garvey JS, Hood L. Distinct hypomyelinated phenotypes in MBP-SV40 large T transgenic mice. J Neurosci Res. 1993 Feb 15;34(3):257–264. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed]
  • Monuki ES, Kuhn R, Weinmaster G, Trapp BD, Lemke G. Expression and activity of the POU transcription factor SCIP. Science. 1990 Sep 14;249(4974):1300–1303. [PubMed]
  • Weinstein DE, Burrola PG, Lemke G. Premature Schwann cell differentiation and hypermyelination in mice expressing a targeted antagonist of the POU transcription factor SCIP. Mol Cell Neurosci. 1995 Jun;6(3):212–229. [PubMed]
  • Bradel EJ, Prince FP. Cultured neonatal rat oligodendrocytes elaborate myelin membrane in the absence of neurons. J Neurosci Res. 1983;9(4):381–392. [PubMed]
  • Rome LH, Bullock PN, Chiappelli F, Cardwell M, Adinolfi AM, Swanson D. Synthesis of a myelin-like membrane by oligodendrocytes in culture. J Neurosci Res. 1986;15(1):49–65. [PubMed]
  • Knapp PE, Bartlett WP, Skoff RP. Cultured oligodendrocytes mimic in vivo phenotypic characteristics: cell shape, expression of myelin-specific antigens, and membrane production. Dev Biol. 1987 Apr;120(2):356–365. [PubMed]
  • Notterpek LM, Rome LH. Functional evidence for the role of axolemma in CNS myelination. Neuron. 1994 Aug;13(2):473–485. [PubMed]
  • Gow A, Friedrich VL, Jr, Lazzarini RA. Myelin basic protein gene contains separate enhancers for oligodendrocyte and Schwann cell expression. J Cell Biol. 1992 Nov;119(3):605–616. [PMC free article] [PubMed]
  • Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. [PubMed]
  • Wegner M, Drolet DW, Rosenfeld MG. Regulation of JC virus by the POU-domain transcription factor Tst-1: implications for progressive multifocal leukoencephalopathy. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4743–4747. [PMC free article] [PubMed]
  • Renner K, Sock E, Gerber JK, Wegner M. T antigen of human papovavirus JC stimulates transcription of the POU domain factor Tst-1/Oct6/SCIP. DNA Cell Biol. 1996 Dec;15(12):1057–1062. [PubMed]
  • Kamholz JA. Regulation of myelin development. Mult Scler. 1996 Dec;2(5):236–240. [PubMed]

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