Cell
Volume 71, Issue 4, 13 November 1992, Pages 565-576
Journal home page for Cell

Article
Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons

https://doi.org/10.1016/0092-8674(92)90591-YGet rights and content

Abstract

We have used homologous recombination in embryonic stem cells to generate mice carrying a mutation in the gene encoding P0, an immunoglobulin-related recognition molecule and the major protein of peripheral nervous system myelin. These mice are deficient in normal motor coordination and exhibit tremors and occasional convulsions. Axons in their peripheral nerves are severely hypomyelinated and a subset of myelin-like figures and axons degenerate. The mutation leads to an abnormal regulation of some, but not all, molecules involved in myelination. These results demonstrate that P0 is essential for the normal spiraling, compaction, and maintenance of the peripheral myelin sheath and the continued integrity of associated axons. They further suggest that this protein conveys a signal that regulates Schwann cell gene expression.

References (64)

  • R. Martini et al.

    Immunocytological localization of the major peripheral nervous system glycoprotein P0 and the L2/HNK-1 and L3 carbohydrate structures in developing and adult mouse sciatic nerve

    Dev. Biol.

    (1988)
  • A. Messing et al.

    P0 promoter directs expression of reporter and toxin genes to Schwann cells of transgenic mice

    Neuron

    (1992)
  • J. Nieke et al.

    Expression of the neural cell adhesion molecules L1 and N-CAM and their common carbohydrate epitope L2/HNK-1 during development and after transection of the mouse sciatic nerve

    Differentiation

    (1985)
  • A. Noronha et al.

    Molecular specificity of L2 monoclonal antibodies that bind to carbohydrate determinants of neural cell adhesion molecules and their resemblance to other monoclonal antibodies recognizing the myelin-associated glycoprotein

    Brain Res.

    (1986)
  • N.T. Potter et al.

    Immunochemical characterization of antibodies to the myelin proteolipid protein (PLP)

    J. Neuroimmunol.

    (1988)
  • U. Schuch et al.

    Neural cell adhesion molecules influence second messenger systems

    Neuron

    (1989)
  • P. Soriano et al.

    Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice

    Cell

    (1991)
  • G. Weskamp et al.

    Evidence that the biological activity of NGF is mediated through a novel subclass of high affinity receptors

    Neuron

    (1991)
  • K.-H. You et al.

    DNA sequence, genomic organization, and chromosomal localization of the mouse peripheral myelin protein zero gene: identification of polymorphic alleles

    Genomics

    (1991)
  • J.L. Bixby et al.

    Extracellular matrix molecules and cell adhesion molecules induce neurite outgrowth through different mechanisms

    J. Cell Biol.

    (1990)
  • H. Büeler et al.

    Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein

    Nature

    (1992)
  • M.R. Capecchi

    Altering the genome by homologous recombination

    Science

    (1989)
  • M. Cervello et al.

    Phosphorylation-dependent regulation of axon fasciculation

  • B.A. Cunningham et al.

    Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative splicing

    Science

    (1987)
  • G.M. Edelman et al.

    Cell adhesion molecules: implications for a molecular histology

    Annu. Rev. Biochem.

    (1991)
  • T. Fahrig et al.

    Two monoclonal antibodies recognizing carbohydrate epitopes on neural adhesion molecules interfere with cell interactions

    Eur. J. Neurosci.

    (1990)
  • A. Faissner et al.

    Biosynthesis and membrane topology of the neural cell adhesion molecule L1

    EMBO J.

    (1985)
  • M.T. Filbin et al.

    Role of myelin P0 protein as a homophilic adhesion molecule

    Nature

    (1990)
  • T. Frei et al.

    Different extracellular domains of the neural adhesion molecule N-CAM are involved in different functions

    J. Cell Biol.

    (1992)
  • S. Greenfield et al.

    Protein composition of myelin of the peripheral nervous system

    J. Neurochem.

    (1973)
  • P. Hasty et al.

    Target frequency and integration pattern for insertion and replacement vectors in embryonic stem cells

    Mol. Cell. Biol.

    (1991)
  • S. Hoffman et al.

    Kinetics of homophilic binding by embryonic and adult forms of the neural cell adhesion molecule

  • Cited by (472)

    • Targeting the programmed axon degeneration pathway as a potential therapeutic for Charcot-Marie-Tooth disease

      2020, Brain Research
      Citation Excerpt :

      CMT1B is caused by numerous different point mutations that are predominantly localized within the extracellular domain of the MPZ protein (Sanmaneechai et al., 2015). Several mutations have been suggested to be pathogenic due to loss of function, which is supported by the presence of CMT1B-like symptoms in MPZ knockout mice (Giese et al., 1992; Martini et al., 1995). These mice exhibit demyelination, impaired nerve conduction, axon degeneration and abnormal motor function similar to CMT1B patients (Giese et al., 1992; Martini et al., 1995; Martini, 1999).

    View all citing articles on Scopus
    View full text