Absence of P0 leads to the dysregulation of myelin gene expression and myelin morphogenesis

P0, the major peripheral nervous system (PNS) myelin protein, is a member of the immunoglobulin supergene family of membrane proteins and can mediate homotypic adhesion. P0 is an essential structural component of PNS myelin; mice in which P0 expression has been eliminated by homologous recombination (P0−/−) develop a severe dysmyelinating neuropathy with predominantly uncompacted myelin. Although P0 is thought to play a role in myelin compaction by promoting adhesion between adjacent extracellular myelin wraps, as an adhesion molecule it could also have a regulatory function. Consistent with this hypothesis, Schwann cells in adult P0−/− mice display a novel molecular phenotype: PMP22 expression is down‐regulated, MAG and PLP expression are up‐regulated, and MBP expression is unchanged. As in quaking viable mutant mice (qkv), which have uncompacted myelin morphologically similar to that found in P0−/− mice, neither the qKI‐6 or qKI‐7 proteins are expressed in P0−/− peripheral nerve. In addition to these changes in gene expression in the P0 knockout, PLP/DM‐20 accumulates in the endoplasmic reticulum of P0−/− Schwann cells, whereas MAG accumulates in redundant loops of uncompacted myelin, not at nodes of Ranvier or Schmidt‐Lantermann incisures. Taken together, these results demonstrate that P0 is involved, either directly or indirectly, in the regulation of both myelin gene expression and myelin morphogenesis. J. Neurosci. Res. 60:714–724, 2000. © 2000 Wiley‐Liss, Inc.

[1]  M. Schachner,et al.  Localization and functional roles of PMP22 in peripheral nerves of P0‐deficient mice , 1999, Glia.

[2]  M. Schachner,et al.  Subtle roles of neural cell adhesion molecule and myelin‐associated glycoprotein during Schwann cell spiralling in P0‐deficient mice , 1999, Glia.

[3]  H. Müller,et al.  Peripheral Myelin Protein 22 and Protein Zero: a Novel Association in Peripheral Nervous System Myelin , 1999, The Journal of Neuroscience.

[4]  A. Zorn,et al.  The KH domain protein encoded by quaking functions as a dimer and is essential for notochord development in Xenopus embryos. , 1997, Genes & development.

[5]  G. Kraft,et al.  Proteolipid Protein Is Necessary in Peripheral as Well as Central Myelin , 1997, Neuron.

[6]  K. Artzt,et al.  Neural Cell Type-Specific Expression of QKI Proteins Is Altered in quakingviable Mutant Mice , 1996, The Journal of Neuroscience.

[7]  M. Filbin,et al.  Dominant-negative effect on adhesion by myelin Po protein truncated in its cytoplasmic domain , 1996, The Journal of cell biology.

[8]  W. Hendrickson,et al.  Crystal Structure of the Extracellular Domain from P0, the Major Structural Protein of Peripheral Nerve Myelin , 1996, Neuron.

[9]  J. Lupski,et al.  Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination , 1996, Neuron.

[10]  A. Brice,et al.  Ultrastructural PMP22 expression in inherited demyelinating neuropathies , 1996, Annals of neurology.

[11]  M. Yoshida,et al.  Parallel Evolution and Coexpression of the Proteolipid Proteins and Protein Zero in Vertebrate Myelin , 1996, Neuron.

[12]  K. Nave,et al.  A Transgenic Rat Model of Charcot-Marie-Tooth Disease , 1996, Neuron.

[13]  T. Gibson,et al.  Three-Dimensional Structure and Stability of the KH Domain: Molecular Insights into the Fragile X Syndrome , 1996, Cell.

[14]  M. Justice,et al.  The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins , 1996, Nature Genetics.

[15]  A. Aguzzi,et al.  Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice , 1995, Nature Genetics.

[16]  D. D'urso,et al.  Protein zero, a nervous system adhesion molecule, triggers epithelial reversion in host carcinoma cells , 1995, The Journal of cell biology.

[17]  T. Schedl,et al.  Mutations in gld-1, a female germ cell-specific tumor suppressor gene in Caenorhabditis elegans, affect a conserved domain also found in Src-associated protein Sam68. , 1995, Genes & development.

[18]  D. Sherman,et al.  Novel E-cadherin-mediated adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions [published erratum appears in J Cell Biol 1995 Jun;129(6):1721] , 1995, The Journal of cell biology.

[19]  P. Morell,et al.  NGFR-mRNA expression in sciatic nerve: a sensitive indicator of early stages of axonopathy. , 1995, Brain research. Molecular brain research.

[20]  M. Filbin,et al.  The cytoplasmic domain of the myelin P0 protein influences the adhesive interactions of its extracellular domain , 1994, The Journal of cell biology.

[21]  V. Quaranta,et al.  Beta 4 integrin expression in myelinating Schwann cells is polarized, developmentally regulated and axonally dependent. , 1994, Development.

[22]  D. Pleasure,et al.  Developmental expression of P0 mRNA and P0 protein in the sciatic nerve and the spinal nerve roots of the rat , 1994, Journal of neurocytology.

[23]  J. Kamholz,et al.  Axons regulate Schwann cell expression of the POU transcription factor SCIP , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  E. Shooter,et al.  Rapid Communication: Human Peripheral Myelin Protein‐22 Carries the L2/HNK‐1 Carbohydrate Adhesion Epitope , 1993, Journal of neurochemistry.

[25]  M. Filbin,et al.  Homophilic adhesion of the myelin P0 protein requires glycosylation of both molecules in the homophilic pair , 1993, The Journal of cell biology.

[26]  Peter Walter,et al.  Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase , 1993, Cell.

[27]  D. Pleasure,et al.  Appearance of PLP mRNA in Specific Regions of the Developing Rat Lumbosacral Spinal Cord as Revealed by in Situ Hybridization , 1993, Experimental Neurology.

[28]  G. Lemke.  The molecular genetics of myelination: An update , 1993, Glia.

[29]  M. Schachner,et al.  Mouse P 0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons , 1992, Cell.

[30]  P. Morell,et al.  Primary demyelination induced by exposure to tellurium alters Schwann cell gene expression: a model for intracellular targeting of NGF receptor , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  J. Bonnet,et al.  P0 protein in normal, trembler heterozygous/homozygous mice during active PNS myelination. , 1992, NeuroReport.

[32]  K. Mikoshiba,et al.  Selective Expression of DM‐20, an Alternatively Spliced Myelin Proteolipid Protein Gene Product, in Developing Nervous System and in Nonglial Cells , 1992, Journal of neurochemistry.

[33]  D. Pleasure,et al.  Structure and expression of proteolipid protein in the peripheral nervous system , 1992, Journal of neuroscience research.

[34]  P. Brophy,et al.  Protein zero of peripheral nerve myelin: Biosynthesis, membrane insertion, and evidence for homotypic interaction , 1990, Neuron.

[35]  M. Fournier,et al.  Developmental Expression of the P0 Glycoprotein and Basic Protein mRNAs in Normal and Trembler Mutant Mice , 1989, Journal of neurochemistry.

[36]  G. Sobue,et al.  Regulation of Schwann cell nerve growth factor receptor by cyclic adenosine 3′,5′‐monophosphate , 1988, Journal of neuroscience research.

[37]  J. Kamholz,et al.  Organization and expression of the human myelin basic protein gene , 1988, Journal of neuroscience research.

[38]  B. Trapp.  Distribution of the myelin-associated glycoprotein and P0 protein during myelin compaction in quaking mouse peripheral nerve , 1988, The Journal of cell biology.

[39]  G. Lemke,et al.  Isolation and analysis of the gene encoding peripheral myelin protein zero , 1988, Neuron.

[40]  J. Schweitzer,et al.  Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[41]  R. Mirsky,et al.  Axonal signals regulate the differentiation of non-myelin-forming Schwann cells: an immunohistochemical study of galactocerebroside in transected and regenerating nerves , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  T. Inuzuka,et al.  Myelin‐Associated Glycoprotein in the Central and Peripheral Nervous System of Quaking Mice , 1987, Journal of neurochemistry.

[43]  J. Salzer,et al.  The amino acid sequences of the myelin-associated glycoproteins: homology to the immunoglobulin gene superfamily , 1987, The Journal of cell biology.

[44]  R. Mirsky,et al.  Distribution of the adhesion molecules N-CAM and L1 on peripheral neurons and glia in adult rats , 1986, Journal of neurocytology.

[45]  H. Clark,et al.  Induction of nerve growth factor receptor in Schwann cells after axotomy. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[46]  C. Dani,et al.  Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. , 1985, Nucleic acids research.

[47]  R. Axel,et al.  Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin , 1985, Cell.

[48]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[49]  H. Towbin,et al.  Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[50]  P. Morell,et al.  PROTEIN COMPOSITION OF MYELIN OF THE PERIPHERAL NERVOUS SYSTEM , 1973, Journal of neurochemistry.

[51]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[52]  P. Walter,et al.  Intracellular signaling from the endoplasmic reticulum to the nucleus. , 1998, Annual review of cell and developmental biology.

[53]  J. Lupski,et al.  Myelin protein zero (MPZ) gene mutations in nonduplication type 1 Charcot‐Marie‐Tooth disease , 1996, Human mutation.

[54]  G. Wilkin,et al.  Up-regulation of GAP-43 and growth of axons in rat spinal cord after compression injury , 1993, Journal of neurocytology.

[55]  S. Scherer,et al.  Axons modulate the expression of transforming growth factor‐betas in Schwann cells , 1993, Glia.