Neurodegeneration Induced by De-Regulation of Neurofilament Gene Expression in Transgenic Mice

  • J.-P. Julien
  • F. Côté
  • G. Charron
  • J.-F. Collard
Part of the Altschul Symposia Series book series (ALSS, volume 3)


Neurofilaments (NFs) are formed by the copolymerization of three proteins, the light (NF-L), medium (NF-M) and heavy (NF-H) subunits (Hoffman and Lasek,1975; Liem et al., 1978). The three NF subunits are encoded by different genes and several reports have shown that the genes are under separate developmental control (Shaw and Weber, 1982; Carden et al., 1987; Cochard and Paulin, 1984; Julien et al., 1986). Direct evidence for a role of neurofilaments in the control of axonal calibers was recently provided from the recent analyses of a mutant quail (Ohara et al. 1993) and of a transgenic mouse (Eyer and Peterson 1994) with NF-deficient axons.


Amyotrophic Lateral Sclerosis Axonal Transport Amyotrophic Lateral Sclerosis Patient Motor Neuron Disease Spinal Motor Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Beaudet L, Charron G, Houle D, Tretjakoff I, Peterson A and Julien J.-P. (1992): Intragenic regulatory elements contribute to transcriptional control of the neurofilament light gene. Gene 116: 205–214,.PubMedCrossRefGoogle Scholar
  2. Carden MJ, Trojanowski JQ, Schlaepfer WW and Lee, VM-Y (1987): Two-stage expression of neurofilament polypeptides during rat neurogenesis with early establishment of adult phosphorylation patterns. J Neurosci 7: 3489–3504.PubMedGoogle Scholar
  3. Carpenter S (1968): Proximal enlargement in motor neuron diseases. Neurol 18: 841–851.CrossRefGoogle Scholar
  4. Chou SM (1992): Pathology - Light microscopy of amyotrophic lateral sclerosis. In Smith RA (ed): “Handbook of Amyotrophic Lateral Sclerosis,” Marcel Dekker Inc, New York, 133–181.Google Scholar
  5. Carpenter S Karpati G Andermann F and Gold R (1974): Giant axonal neuropathy: a clinically and morphologically distinct neurological disease. Arch Neurol 31: 312.PubMedCrossRefGoogle Scholar
  6. Cochard P and Paulin D (1984): Initial expression of neurofilament and vimentin in the central and peripheral nervous system of the mouse embryo in vivo, J Neurosci 4: 2080–2094.PubMedGoogle Scholar
  7. Collard JF and Julien JP (1994): A simple test to monitor motor dysfunction in a transgenic mouse model of amyotrophic lateral sclerosis. J Psychiatry and Neuroscience (in press).Google Scholar
  8. Côté F, Collard J-F and Julien J-P (1993): Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: A mouse model of amyotrophic lateral sclerosis. Cell 73: 35–47.PubMedCrossRefGoogle Scholar
  9. Côté F, Collard J-F, Houle D and Julien J-P (1994): Copy-dependent and correct developmental expression of the human neurofilament heavy gene in transgenic mice. Molec Brain Res 26: 99–105.Google Scholar
  10. Eyer J and Peterson A (1994): Neurofilament-deficient axons and perikaryal aggregates in viable transgenic mice expressing a neurofilament-beta-galactosidase fusion protein. Neuron 12: 389–416.PubMedCrossRefGoogle Scholar
  11. Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Klein V, Rouleau GA and Julien J-P (1993): Variants of the heavy neurofilament gene subunit are associated with the development of amyotrophic lateral sclerosis. Hum Molec Genet 3: 1757–1761.CrossRefGoogle Scholar
  12. Gajdusek DC (1985): Hypothesis: interference with axonal transport of neurofilament as a common pathogenetic mechanism of certain diseases of the CNS. N Engl J Med 312: 714–719.PubMedCrossRefGoogle Scholar
  13. Graham DG, Szakal-Quin G, Priest JW and Anthony DC (1984): In vitro evidence that covalent crosslinking of neurofilaments occurs in gamma-diketone neuropathy. Proc Natl Acad Sci USA 81: 4979–4982.CrossRefGoogle Scholar
  14. Griffin JW, Hoffman PN, Clark AW, Carroll PT and Price DL (1978): Slow axonal transport of neurofilament proteins: Impairment by ß,ß’-iminodipropionitrile administration. Science 202: 633–635.PubMedCrossRefGoogle Scholar
  15. Griffin JW and Watson DF (1988): Axonal transport in neurological disease. Ann Neurol 23: 3–13.PubMedCrossRefGoogle Scholar
  16. Hirano A, Donnenfeld H, Sasaki S and Nakano I (1984): Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43: 461–470.CrossRefGoogle Scholar
  17. Hirano A and Kato S (1992): Fine structural study of sporadic and familial amyotrophic lateral sclerosis. In Smith RA (ed): “Handbook of Amyotrophic Lateral Sclerosis,” Marcel Dekker Inc, New York, 183–192.Google Scholar
  18. Hoffman PN and Lasek RJ (1975): The slow component of axonal transport. Identification of the major structural polypeptides of the axon and their generality among mammalian neurons. J Cell Biol 66: 351–366.PubMedCrossRefGoogle Scholar
  19. Ivanov TR and Brown IR (1992): Interaction of multiple nuclear proteins with the promoter region of the mouse 68-kDa neurofilament gene. J Neurosci 32: 149–158.CrossRefGoogle Scholar
  20. Julien J-P, Meijer D, Hurst J and Grosveld F (1986): Cloning and developmental expression of the murine neurofilament gene family. Mol Brain Res 1: 243–250.CrossRefGoogle Scholar
  21. Julien J-P, Tretjakoff I, Beaudet L and Peterson A (1987): Expression and assembly of a human neurofilament protein in transgenic mice provide a novel neuronal marking system. Genes Dev 1: 1085–1095.PubMedCrossRefGoogle Scholar
  22. Julien JP, Grosveld F, Yazdanbajksh K, Flavell D, Meijen D and Mushynski W (1987): Structure of the human neurofilament light gene (NF-L): a unique exon-intron organization in the intermediate filament gene family. Biochem Biophys Acta 909: 10–20.PubMedCrossRefGoogle Scholar
  23. Julien JP, Côté F, Beaudet L, Sidky M Flavell D, Grosveld F and Mushynski W (1988): Sequence and structure of the mouse gene coding for the largest neurofilament subunit. Gene 68: 307–314.PubMedCrossRefGoogle Scholar
  24. Lees JF, Shneidman PS, Skuntz SF, Carden MJ and Lazzarini RA (1988): The structure and organization of the human heavy neurofilament subunit (NF-H) and the gene encoding it. EMBO J 7: 1947–1955.PubMedGoogle Scholar
  25. Levy E, Liem RKU, D’Eustachio P and Cowan NJ (1982): Structure and evolutionary origin of the gene encoding mouse NF-M, the middle molecular mass neurofilament protein. Eur J Biochem 166: 71–72.CrossRefGoogle Scholar
  26. Liem RKH, Yen S-H, Salomon GD and Shelanski ML (1978): Intermediate filaments in nervous tissues. J Cell Biol 79: 637–645.PubMedCrossRefGoogle Scholar
  27. Lindenbaum MH, Carbonetto S, Grosveld F, Flavell D and Mushynski WE (1988): Transcriptional and post-transcriptional effects of nerve growth factor on expression of the three neurofilament subunits in PC-12 cells. J Biol Chem 263: 5662–5667.PubMedGoogle Scholar
  28. Monteiro MJ, Hoffman PN, Gearhart JD and Cleveland DW (1990): Expression of NF-L in both neuronal and nonneuronal cells of transgenic mice: increased neurofilament density in axons without affecting caliber. J Cell Biol 111: 1543–1557.PubMedCrossRefGoogle Scholar
  29. Muma NA and Cork LC (1993): Alternations in neurofilament mRNA in hereditary canine spinal muscular atrophy. Lab Invest 69: 436–442.PubMedGoogle Scholar
  30. Nakahira K, Ikenaha K, Wada K, Tamura T, Furuichi T and Mikoshiba K (1990): Structure of the 68 kDa neurofilament gene and regulation of its expression. J Biol Chem 265: 19786–19791.PubMedGoogle Scholar
  31. Ohara O, Gahara Y, Miyake T, Teraoka H and Kitamura T (1993): Neurofilament deficiency in quail caused by nonsense mutation in neurofilament-L gene. J Cell Biol 121: 387–395.PubMedCrossRefGoogle Scholar
  32. Rosen DR, Siddique T, Patterson D, Figlewicz DA, et al. (1993): Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62.PubMedCrossRefGoogle Scholar
  33. Sasaki S, Murayana S, Yamane K, Sakuma H and Takeishi M (1989): Swelling of proximal axons in a case of motor neuron disease. Ann Neurol 25: 520–522.PubMedCrossRefGoogle Scholar
  34. Schmidt ML, Carden MJ, Lee VM-Y and Trojanowski JQ (1987): Phosphate dependent and independent neurofilament epitopes in the axonal swellings of patients with motor neuron disease and controls. Lab Invest 56: 282–294.PubMedGoogle Scholar
  35. Schneidman PS, Bruce J, Schwartz ML and Schlaepfer WW (1992): Negative regulatory regions are present upstream in the three mouse neurofilament genes. Molec Brain Res 13: 127–138.CrossRefGoogle Scholar
  36. Shaw G and Weber K (1982): Differential expression of neurofilament triplet proteins in brain development. Nature 298: 277–279.PubMedCrossRefGoogle Scholar
  37. Troncoso JC, Gilbert MR and Muma NA (1992): Neurotoxicology: light metals, In Smith RA (ed): “Handbook of Amyotrophic Lateral Sclerosis,” Marcel Dekker Inc, New York, 543–558.Google Scholar
  38. Tsuneishi S, Sano K and Nakamura H (1993): Serum depletion increases the neurofilament protein mRNA levels in a neuroblastoma cell line, GOTO. Molec Brain Res 17: 119–128.PubMedCrossRefGoogle Scholar
  39. Xu Z, Cork LC, Griffin JW and Cleveland DW (1993): Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell 73: 23–33.PubMedCrossRefGoogle Scholar
  40. Yazdanbakhsh K, Fraser P, Kioussis D, Vidal M, Grosveld F and Lindenbaum M (1993): Functional analysis of the human neurofilament light chain gene promoter. Nucl Acids Res 21: 455–461.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • J.-P. Julien
    • 1
  • F. Côté
    • 1
  • G. Charron
    • 1
  • J.-F. Collard
    • 1
  1. 1.Centre for Research in Neuroscience, McGill UniversityThe Montreal General HospitalMontrealCANADA

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