Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice (original) (raw)

Abstract

The isoproteins proteolipid protein (PLP) and DM20, the two major integral membrane proteins of central nervous system (CNS) myelin, are encoded by a single gene on the X chromosome and show a different developmental expression pattern. To investigate their functions in myelin structure and myelination, we produced transgenic mice carrying a targeted alteration of the X chromosome-linked Plp gene containing a deletion within exon III, mimicking DM20, and a neo cassette in reverse orientation within intron III. Here we show that the antisense integration of the neo cassette disrupts the expression of the Plp gene. The ultrastructure of the multilayer myelin sheath of all axons in the CNS of hemizygous male or homozygous female PLP/DM20-deficient mice is highly disordered. The apposition of the extracytoplasmic surfaces and thereby the intraperiod dense line is lacking. The disrupted assembly of the myelin sheath leads to a profound reduction of conductance velocities of CNS axons, impairments in neuromotor coordination, and behavioral changes.

11709

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bradley A., Evans M., Kaufman M. H., Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature. 1984 May 17;309(5965):255–256. doi: 10.1038/309255a0. [DOI] [PubMed] [Google Scholar]
  2. Büssow H. Schwann cell myelin ensheathing C.N.S. axons in the nerve fibre layer of the cat retina. J Neurocytol. 1978 Apr;7(2):207–214. doi: 10.1007/BF01217919. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Derry J. M., Barnard P. J. Mapping of the glycine receptor alpha 2-subunit gene and the GABAA alpha 3-subunit gene on the mouse X chromosome. Genomics. 1991 Jul;10(3):593–597. doi: 10.1016/0888-7543(91)90441-g. [DOI] [PubMed] [Google Scholar]
  5. Diehl H. J., Schaich M., Budzinski R. M., Stoffel W. Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9807–9811. doi: 10.1073/pnas.83.24.9807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Doyle J. P., Colman D. R. Glial-neuron interactions and the regulation of myelin formation. Curr Opin Cell Biol. 1993 Oct;5(5):779–785. doi: 10.1016/0955-0674(93)90025-l. [DOI] [PubMed] [Google Scholar]
  7. Ikenaka K., Kagawa T., Mikoshiba K. Selective expression of DM-20, an alternatively spliced myelin proteolipid protein gene product, in developing nervous system and in nonglial cells. J Neurochem. 1992 Jun;58(6):2248–2253. doi: 10.1111/j.1471-4159.1992.tb10970.x. [DOI] [PubMed] [Google Scholar]
  8. Inouye H., Kirschner D. A. Folding and function of the myelin proteins from primary sequence data. J Neurosci Res. 1991 Jan;28(1):1–17. doi: 10.1002/jnr.490280102. [DOI] [PubMed] [Google Scholar]
  9. Kitagawa K., Sinoway M. P., Yang C., Gould R. M., Colman D. R. A proteolipid protein gene family: expression in sharks and rays and possible evolution from an ancestral gene encoding a pore-forming polypeptide. Neuron. 1993 Sep;11(3):433–448. doi: 10.1016/0896-6273(93)90148-k. [DOI] [PubMed] [Google Scholar]
  10. Nave K. A., Lai C., Bloom F. E., Milner R. J. Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5665–5669. doi: 10.1073/pnas.84.16.5665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Nellen W., Lichtenstein C. What makes an mRNA anti-sense-itive? Trends Biochem Sci. 1993 Nov;18(11):419–423. doi: 10.1016/0968-0004(93)90137-c. [DOI] [PubMed] [Google Scholar]
  12. Pham-Dinh D., Boespflug-Tanguy O., Mimault C., Cavagna A., Giraud G., Leberre G., Lemarec B., Dautigny A. Pelizaeus-Merzbacher disease: a frameshift deletion/insertion event in the myelin proteolipid gene. Hum Mol Genet. 1993 Apr;2(4):465–467. doi: 10.1093/hmg/2.4.465. [DOI] [PubMed] [Google Scholar]
  13. Pontius B. W., Berg P. Renaturation of complementary DNA strands mediated by purified mammalian heterogeneous nuclear ribonucleoprotein A1 protein: implications for a mechanism for rapid molecular assembly. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8403–8407. doi: 10.1073/pnas.87.21.8403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Schaich M., Budzinski R. M., Stoffel W. Cloned proteolipid protein and myelin basic protein cDNA. Transcription of the two genes during myelination. Biol Chem Hoppe Seyler. 1986 Aug;367(8):825–834. doi: 10.1515/bchm3.1986.367.2.825. [DOI] [PubMed] [Google Scholar]
  15. Schliess F., Stoffel W. Evolution of the myelin integral membrane proteins of the central nervous system. Biol Chem Hoppe Seyler. 1991 Sep;372(9):865–874. doi: 10.1515/bchm3.1991.372.2.865. [DOI] [PubMed] [Google Scholar]
  16. Stoffel W., Hillen H., Giersiefen H. Structure and molecular arrangement of proteolipid protein of central nervous system myelin. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5012–5016. doi: 10.1073/pnas.81.16.5012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Timsit S. G., Bally-Cuif L., Colman D. R., Zalc B. DM-20 mRNA is expressed during the embryonic development of the nervous system of the mouse. J Neurochem. 1992 Mar;58(3):1172–1175. doi: 10.1111/j.1471-4159.1992.tb09378.x. [DOI] [PubMed] [Google Scholar]
  18. Weimbs T., Stoffel W. 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. Biochemistry. 1992 Dec 15;31(49):12289–12296. doi: 10.1021/bi00164a002. [DOI] [PubMed] [Google Scholar]