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Gene Review

Nefl  -  neurofilament, light polypeptide

Rattus norvegicus

Synonyms: 68 kDa neurofilament protein, NF-L, Neurofilament light polypeptide, Neurofilament triplet L protein, Nf68, ...
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Disease relevance of Nefl


High impact information on Nefl

  • The 66 kd protein constituted 0.5% of total protein in the spinal cord, whereas NF-L constituted about 1.5% [5].
  • To examine this and to further investigate the function of the carboxyl-terminal tail domain of NF-M, we made various deletion mutants that lacked part of their tail domains, and we expressed these with NF-L [6].
  • We examined the differential expression of genes encoding three beta-tubulin isotypes (classes I, II, and IV) and the 68-kDa neurofilament protein (NF68) in rat sensory neurons during development, maturation, and axonal regeneration [7].
  • Hybridization with specific cDNAs was used to measure levels of mRNA encoding the 68-kDa neurofilament protein (NF68), beta-tubulin, and actin in lumbar sensory neurons of rat at various times after crushing the sciatic nerve [8].
  • Within 24 hr of axotomy, there was a down-regulation of the 68 kDa (NF-L) and 145 kDa (NF-M) NF subunits [9].

Chemical compound and disease context of Nefl

  • The activation of cyclic AMP-dependent protein kinase (PKA) in rat dorsal root ganglion (DRG) cultures increased phosphorylation of the low-molecular-mass neurofilament subunit (NFL) at a site previously identified as Ser55 but had no effect on neurofilament integrity [10].
  • Intraocular injection of NMDA caused substantial reductions in the mRNA levels of the ganglion cell-specific markers Thy-1 and neurofilament light (NF-L) [3].
  • Terbutaline administered on postnatal days PN2 to 5 elicited neurochemical changes indicative of neuronal injury and reactive gliosis: immediate increases in glial fibrillary acidic protein and subsequent induction of the 68-kDa neurofilament protein [11].
  • To investigate the mechanism of diminished NF content, subunit (NF-L, -M and -H) gene expression was quantified in dorsal root ganglion (DRG) of slightly affected and moderately intoxicated groups of rats exposed to 2,5-hexanedione (HD) at one of three daily dosing rates (175, 250 and 400 mg/kg per day) [12].

Biological context of Nefl

  • For functional analysis of the NF-L promoter, constructs carrying 38, 97, 407, 564, 650, 1,099, 1,660, 2,003 base pairs (bp) upstream region in front of the chloramphenicol acetyltransferase (CAT) reporter gene were tested for their capability to direct CAT expression after transient transfection into various cell lines [13].
  • Identification of serine 473 as a major phosphorylation site in the neurofilament polypeptide NF-L [14].
  • An "immature" form of NFs, composed of NF-M and NF-L, appears to function in establishing the neuronal phenotype and in initiating and maintaining neurite outgrowth [15].
  • Restoration of axonal contact in the growing nerve stimulates the recapitulation of Schwann cell differentiation including the elevation of NF-M and NF-L mRNA expression [16].
  • Detection of NF-L and NF-M mRNA in injured nerve, however, indicated that there was an up-regulation in response to nerve injury [17].

Anatomical context of Nefl

  • The role of these factors in NF-L gene transcriptional induction by NGF in PC12 cells is discussed [13].
  • NF-L in optic nerve extract was quantified by quantitative immunoblot using an imaging analyzer [1].
  • Moreover, serine 473 is a major phosphorylation site in vivo; in neurofilaments isolated from rat spinal cord, approximately 73% of serine 473 was phosphorylated, and accounted for at least one-third of the total phosphate associated with NF-L [14].
  • Compared with age-matched controls, neurofilament heavy (NF-H) (3.3-fold) and neurofilament medium (NF-M) (2.5-fold), but not neurofilament light (NF-L), subunits accumulated in the proximal axon of sensory neurons of the lumbar dorsal root ganglia (DRG) in untreated diabetic rats [18].
  • The developmentally regulated intracellular intermediate filament protein neurofilament (NF), composed of the light (NF-L), medium (NF-M) and high (NF-H) molecular weight isoforms, is expressed abundantly in nerve cells but its significance in nerve cell survival in stress situations in the brain is unknown [19].

Associations of Nefl with chemical compounds

  • The amount of NF-L in the optic nerve was significantly reduced in kainate-treated eyes (vs. normal eyes) [1].
  • We report here that serine 473, in the carboxy-terminal tail domain of NF-L, is a major substrate in vitro for protein kinases endogenous to a crude cytoskeleton-containing fraction [14].
  • Chronic, but not acute, administration of either morphine or cocaine was found to decrease levels of the three NF proteins, NF-200 (NF-H), NF-160 (NF-M), and NF-68 (NF-L), by between 15% and 50% in the VTA by back phosphorylation, immunolabeling, and Coomassie blue staining [20].
  • Here we used techniques for the mass spectrometric sequencing of proteins from polyacrylamide gels to analyze in vivo phosphorylation sites on NF-M and NF-L [21].
  • NF-M and NF-L are known to be modified by O-linked N-acetylglucosamine (O-GlcNAc) (Dong, D. L.-Y., Xu, Z.-S., Chevrier, M. R., Cotter, R. J., Cleveland, D. W., and Hart, G. W. (1993) J. Biol. Chem. 268, 16679-16687) [22].

Other interactions of Nefl


Analytical, diagnostic and therapeutic context of Nefl

  • In situ hybridization showed that NF-L mRNA was localized in the Schwann cell perinuclear area, in the myelin sheath, and at the boundary between myelin sheath and cortical axoplasm [17].
  • RT-PCR demonstrated the presence of NF-L, NF-M and NF-H mRNAs in intact sciatic nerve, as well as in proximal and distal stumps of severed nerves [17].
  • Electrophoretic mobility shift assays confirmed these results but showed that the nuclear proteins induced by PKA which bound to the NF-L promoter Sp1-like sequence were not Sp1 [27].
  • Northern blotting revealed that NF-L and NF-M mRNAs were present at very low levels in embryonic brain and that significant expression of these genes only occurred postnatally when the levels increased dramatically until P28 and then declined again in the adult [28].
  • Compared to that of the control group, the levels of NF-L increased respectively by 104% and 45% (P<0.01) in the supernatant and decreased by 16% and 11% (P<0.01) in the pellet of rat cerebrums in lower and higher groups [29].


  1. Alterations in neurofilament light in optic nerve in rat kainate and monkey ocular hypertension models. Taniguchi, T., Shimazawa, M., Hara, H. Brain Res. (2004) [Pubmed]
  2. The calpain inhibitor MDL 28170 prevents inflammation-induced neurofilament light chain breakdown in the spinal cord and reduces thermal hyperalgesia. Kunz, S., Niederberger, E., Ehnert, C., Coste, O., Pfenninger, A., Kruip, J., Wendrich, T.M., Schmidtko, A., Tegeder, I., Geisslinger, G. Pain (2004) [Pubmed]
  3. Effects of intraocular injection of a low concentration of zinc on the rat retina. Nakamichi, N., Chidlow, G., Osborne, N.N. Neuropharmacology (2003) [Pubmed]
  4. Sequencing of the rat light neurofilament promoter reveals differences in methylation between expressing and non-expressing cell lines, but not tissues. Reeben, M., Myöhänen, S., Saarma, M., Prydz, H. Gene (1995) [Pubmed]
  5. Characterization of a novel 66 kd subunit of mammalian neurofilaments. Chiu, F.C., Barnes, E.A., Das, K., Haley, J., Socolow, P., Macaluso, F.P., Fant, J. Neuron (1989) [Pubmed]
  6. Two distinct functions of the carboxyl-terminal tail domain of NF-M upon neurofilament assembly: cross-bridge formation and longitudinal elongation of filaments. Nakagawa, T., Chen, J., Zhang, Z., Kanai, Y., Hirokawa, N. J. Cell Biol. (1995) [Pubmed]
  7. Neurofilament and tubulin expression recapitulates the developmental program during axonal regeneration: induction of a specific beta-tubulin isotype. Hoffman, P.N., Cleveland, D.W. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  8. Neurofilament gene expression: a major determinant of axonal caliber. Hoffman, P.N., Cleveland, D.W., Griffin, J.W., Landes, P.W., Cowan, N.J., Price, D.L. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  9. Axo-glial interactions at the dorsal root transitional zone regulate neurofilament protein synthesis in axotomized sensory neurons. Liuzzi, F.J., Tedeschi, B. J. Neurosci. (1992) [Pubmed]
  10. Activation of cyclic AMP-dependent protein kinase in okadaic acid-treated neurons potentiates neurofilament fragmentation and stimulates phosphorylation of Ser2 in the low-molecular-mass neurofilament subunit. Giasson, B.I., Cromlish, J.A., Athlan, E.S., Mushynski, W.E. J. Neurochem. (1996) [Pubmed]
  11. Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex. Rhodes, M.C., Seidler, F.J., Abdel-Rahman, A., Tate, C.A., Nyska, A., Rincavage, H.L., Slotkin, T.A. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  12. Gamma-diketone peripheral neuropathy III. Neurofilament gene expression. Opanashuk, L.A., He, D.K., Lehning, E.J., LoPachin, R.M. Neurotoxicology (2001) [Pubmed]
  13. Characterization of the rat light neurofilament (NF-L) gene promoter and identification of NGF and cAMP responsive regions. Reeben, M., Neuman, T., Palgi, J., Palm, K., Paalme, V., Saarma, M. J. Neurosci. Res. (1995) [Pubmed]
  14. Identification of serine 473 as a major phosphorylation site in the neurofilament polypeptide NF-L. Xu, Z.S., Liu, W.S., Willard, M. J. Neurosci. (1990) [Pubmed]
  15. Two-stage expression of neurofilament polypeptides during rat neurogenesis with early establishment of adult phosphorylation patterns. Carden, M.J., Trojanowski, J.Q., Schlaepfer, W.W., Lee, V.M. J. Neurosci. (1987) [Pubmed]
  16. Transient expression of the neurofilament proteins NF-L and NF-M by Schwann cells is regulated by axonal contact. Fabrizi, C., Kelly, B.M., Gillespie, C.S., Schlaepfer, W.W., Scherer, S.S., Brophy, P.J. J. Neurosci. Res. (1997) [Pubmed]
  17. Neurofilament mRNAs are present and translated in the normal and severed sciatic nerve. Sotelo-Silveira, J.R., Calliari, A., Kun, A., Benech, J.C., Sanguinetti, C., Chalar, C., Sotelo, J.R. J. Neurosci. Res. (2000) [Pubmed]
  18. Neurotrophin-3 prevents the proximal accumulation of neurofilament proteins in sensory neurons of streptozocin-induced diabetic rats. Sayers, N.M., Beswick, L.J., Middlemas, A., Calcutt, N.A., Mizisin, A.P., Tomlinson, D.R., Fernyhough, P. Diabetes (2003) [Pubmed]
  19. The calpain inhibitor MDL-28170 and the AMPA/KA receptor antagonist CNQX inhibit neurofilament degradation and enhance neuronal survival in kainic acid-treated hippocampal slice cultures. Lopez-Picon, F.R., Kukko-Lukjanov, T.K., Holopainen, I.E. Eur. J. Neurosci. (2006) [Pubmed]
  20. Neurofilament proteins and the mesolimbic dopamine system: common regulation by chronic morphine and chronic cocaine in the rat ventral tegmental area. Beitner-Johnson, D., Guitart, X., Nestler, E.J. J. Neurosci. (1992) [Pubmed]
  21. Identification of phosphorylation sites on neurofilament proteins by nanoelectrospray mass spectrometry. Betts, J.C., Blackstock, W.P., Ward, M.A., Anderton, B.H. J. Biol. Chem. (1997) [Pubmed]
  22. Cytoplasmic O-GlcNAc modification of the head domain and the KSP repeat motif of the neurofilament protein neurofilament-H. Dong, D.L., Xu, Z.S., Hart, G.W., Cleveland, D.W. J. Biol. Chem. (1996) [Pubmed]
  23. Differential regulation of peripherin and neurofilament gene expression in regenerating rat DRG neurons. Wong, J., Oblinger, M.M. J. Neurosci. Res. (1990) [Pubmed]
  24. Malnutrition induces an increase in intermediate filament protein content of rat cerebral cortex. Paz, M.M., Valente, G.B., Tasca, C.I., de Mattos, A.G., Pureur, R.P. J. Nutr. (1991) [Pubmed]
  25. Oxidative stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells. Ray, S.K., Fidan, M., Nowak, M.W., Wilford, G.G., Hogan, E.L., Banik, N.L. Brain Res. (2000) [Pubmed]
  26. Neuroglial interactions in a model of para-chlorophenylalanine-induced serotonin depletion. Ramos, A.J., Tagliaferro, P., López, E.M., Pecci Saavedra, J., Brusco, A. Brain Res. (2000) [Pubmed]
  27. Transcriptional regulation of neurofilament expression by protein kinase A. White, L.A., Reeben, M., Saarma, M., Whittemore, S.R. J. Neurosci. Res. (1997) [Pubmed]
  28. Developmental patterns of intermediate filament gene expression in the normal hamster brain. Kost, S.A., Chacko, K., Oblinger, M.M. Brain Res. (1992) [Pubmed]
  29. Acrylamide-induced changes in the neurofilament protein of rat cerebrum fractions. Yu, S., Zhao, X., Zhang, T., Yu, L., Li, S., Cui, N., Han, X., Zhu, Z., Xie, K. Neurochem. Res. (2005) [Pubmed]
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