Early Onset of Axonal Degeneration in Double (plp−/−mag−/−) and Hypomyelinosis in Triple (plp−/−mbp−/−mag−/−) Mutant Mice

Double (plp−/−mag−/−) and triple (plp−/−mbp−/−mag−/−) null-allelic mouse lines deficient in proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and myelin basic protein (MBP) were generated and characterized genetically, biochemically, and morphologically including their behavioral capacities. Theplp−/−mag−/− mutant develops a rapidly progressing axon degeneration in CNS with severe cognitive and motor coordinative deficits but has a normal longevity. CNS axons of theplp−/−mbp−/−mag−/− mouse are hypomyelinated and ensheathed by “pseudomyelin” with disturbed protein and complex lipid composition. Theshiverer trait in theplp−/−mbp−/−mag−/− similar to the plp−/−mbp−/− mutant is significantly ameliorated, and its lifespan is considerably prolonged. The longevity of these dysmyelinosis mouse mutants recommends them as suitable models for the long-term evaluation of stem cell therapeutic strategies.

[1]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[2]  Virginia M. Y. Lee,et al.  Myelin-Associated Glycoprotein Is a Myelin Signal that Modulates the Caliber of Myelinated Axons , 1998, The Journal of Neuroscience.

[3]  S. Molineaux,et al.  Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Readhead,et al.  Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage , 1994, Neuron.

[5]  S. M. Sumi,et al.  Brain lipid composition of the shiverer mouse: (genetic defect in myelin development) , 1978, Journal of neurochemistry.

[6]  S. Kahn,et al.  Biochemical Abnormalities in Spinal Cord Myelin and CNS Homogenates in Heterozygotes Affected by the Shiverer Mutation , 1984, Journal of neurochemistry.

[7]  W. Stoffel,et al.  Adhesive properties of proteolipid protein are responsible for the compaction of CNS myelin sheaths , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  B. Trapp,et al.  Myelin-Associated Glycoprotein , 1997 .

[9]  K. Nave,et al.  Assembly of CNS Myelin in the Absence of Proteolipid Protein , 1997, Neuron.

[10]  T. Weimbs,et al.  Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioester-linked cysteine residues and implications for the membrane topology of PLP. , 1992, Biochemistry.

[11]  W. Norton,et al.  MYELINATION IN RAT BRAIN: METHOD OF MYELIN ISOLATION 1 , 1973, Journal of neurochemistry.

[12]  F. Bloom,et al.  Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Rosenbluth.  Peripheral myelin in the mouse mutant Shiverer , 1980, The Journal of comparative neurology.

[14]  M. Schachner,et al.  Absence of the myelin-associated glycoprotein (MAG) and the neural cell adhesion molecule (N-CAM) interferes with the maintenance, but not with the formation of peripheral myelin , 1996, Cell and Tissue Research.

[15]  F E Bloom,et al.  Two forms of 1B236/myelin-associated glycoprotein, a cell adhesion molecule for postnatal neural development, are produced by alternative splicing. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[16]  B. Trapp.  Myelin‐Associated Glycoprotein Location and Potential Functions a , 1990, Annals of the New York Academy of Sciences.

[17]  R. Morris.  Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[18]  B. Campbell,et al.  Motor and reflexive behavior in the aging rat. , 1980, Journal of gerontology.

[19]  A. Frey,et al.  Differential expression of MAG isoforms during development , 1991, Journal of neuroscience research.

[20]  W. Stoffel,et al.  Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G F Chernoff,et al.  Shiverer: an autosomal recessive mutant mouse with myelin deficiency. , 1981, The Journal of heredity.

[22]  K. Nave,et al.  Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. , 1998, Science.

[23]  K. Klapdor,et al.  The Morris Water-Escape Task in Mice: Strain Differences and Effects of Intra-Maze Contrast and Brightness , 1996, Physiology & Behavior.

[24]  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.

[25]  R. McKinnon,et al.  Motor function analysis of myelin mutant mice using a rotarod , 1995, International Journal of Developmental Neuroscience.

[26]  M. Schachner,et al.  Crucial Role for the Myelin‐associated Glycoprotein in the Maintenance of Axon‐Myelin Integrity , 1995, The European journal of neuroscience.

[27]  Naoki Takahashi,et al.  Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice , 1985, Cell.

[28]  W. Stoffel,et al.  Functional analysis in vivo of the double mutant mouse deficient in both proteolipid protein (PLP) and myelin basic protein (MBP) in the central nervous system , 1997, Cell and Tissue Research.

[29]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[30]  K. Nave,et al.  Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene , 1992, Nature.

[31]  K. Mikoshiba,et al.  Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene , 1994, Neuron.

[32]  W. Stoffel,et al.  Myelin‐deficient rat: a point mutation in exon III (A‐‐‐‐C, Thr75‐‐‐‐Pro) of the myelin proteolipid protein causes dysmyelination and oligodendrocyte death. , 1989, The EMBO journal.

[33]  M. Schachner,et al.  The Cytoplasmic Domain of the Large Myelin-associated Glycoprotein Isoform Is Needed for Proper Cns but Not Peripheral Nervous System Myelination , 2022 .

[34]  K. Suzuki,et al.  Gangliosides in the myelin fraction of developing rats. , 1967, Biochimica et biophysica acta.

[35]  E. Barbarese,et al.  The number of Schmidt-Lanterman incisures is more than doubled inshiverer PNS myelin sheaths , 1995, Journal of neurocytology.

[36]  K. Klapdor,et al.  Repeated Acquisition of a Spatial Navigation Task in Mice: Effects of Spacing of Trials and of Unilateral Middle Cerebral Artery Occlusion , 1998, Physiology & Behavior.

[37]  N. Baumann,et al.  Brain Gangliosides of Quaking and Shiverer Mutants: Qualitative and Quantitative Changes of Monosialogangliosides in the Quaking Brain , 1985, Journal of neurochemistry.

[38]  R. Quarles,et al.  Differentiation of oligodendrocytes cultured from developing rat brain is enhanced by exogenous GM3 ganglioside , 1994, Journal of neuroscience research.

[39]  J. Roder,et al.  Differential splicing of MAG transcripts during CNS and PNS development. , 1988, Brain research.

[40]  E. Jacobs,et al.  Identification of a New Exon in the Myelin Proteolipid Protein Gene Encoding Novel Protein Isoforms That Are Restricted to the Somata of Oligodendrocytes and Neurons , 1999, The Journal of Neuroscience.

[41]  J. Riordan,et al.  Over‐Expression of the DM‐20 Myelin Proteolipid Causes Central Nervous System Demyelination in Transgenic Mice , 1995, Journal of neurochemistry.

[42]  P. Braun,et al.  Proteins of Myelin , 1977 .

[43]  J. Roder,et al.  Molecular cloning and primary structure of myelin-associated glycoprotein. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[44]  J. Tateishi,et al.  Radial component of central myelin in shiverer mouse , 1983, Brain Research.

[45]  T. Miyatake,et al.  Expression of the large myelin-associated glycoprotein isoform during the development in the mouse peripheral nervous system , 1991, Brain Research.

[46]  J. Roder,et al.  Myelination in the absence of myelin-associated glycoprotein , 1994, Nature.

[47]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[48]  H. Webster,et al.  Immunocytochemical localization of basic protein in major dense line regions of central and peripheral myelin , 1982, The Journal of cell biology.

[49]  H. Büssow.  Schwann cell myelin ensheathing C.N.S. axons in the nerve fibre layer of the cat retina , 1978, Journal of neurocytology.

[50]  R. Quarles,et al.  Expression of glycolipids and myelin-associated glycoprotein during the differentiation of oligodendrocytes: comparison of the CG-4 glial cell line to primary cultures. , 1995, Developmental neuroscience.

[51]  D. Silberberg,et al.  Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture , 1978, Nature.

[52]  D. Kirschner,et al.  Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. , 1994, Neuron.

[53]  W. Stoffel,et al.  Ceramide UDPgalactosyltransferase from myelinating rat brain: purification, cloning, and expression. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[54]  W. Stoffel,et al.  Structure and molecular arrangement of proteolipid protein of central nervous system myelin. , 1984, Proceedings of the National Academy of Sciences of the United States of America.