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Gene Review

Nefm  -  neurofilament, medium polypeptide

Rattus norvegicus

Synonyms: 160 kDa neurofilament protein, NF-M, Nef3, Neurofilament 3, Neurofilament medium polypeptide, ...
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Disease relevance of Nef3

  • Two-dimensional gel analysis and immunoblotting of total proteins from adult rat dorsal root ganglion verified mAb specificity in situ, and showed that differentially phosphorylated isoforms of NF-M and NF-H occur in vivo [1].
  • The transient induction of NF-M mRNA is also apparent in dedifferentiating Schwann cells during Wallerian degeneration [2].
  • Using antibodies that were directed at all three neurofilament (NF) epitopes, NF-L, NF-M, and NF-H, we attempted to determine whether these neurons would have an altered cytoskeletal profile following the stress of transplantation, because previous studies have shown such changes following ischemia or direct brain injury [3].
  • We examined the short-term regulation of the phosphorylation of the mid-sized neurofilament subunit (NF-M) by kinases which were activated in rat pheochromocytoma (PC12) cells by nerve growth factor (NGF) and/or 12-O-tetradecanoylphorbol 13-acetate (TPA) [4].
  • Phosphorylation of the neuronal cytoskeletal proteins NF-H, NF-M and tau is important for normal axonal development, and is involved in axonal injury and neurodegenerative diseases [5].

High impact information on Nef3

  • 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].
  • These data demonstrate that Schwann cells remodel their IFs by expressing NF-M before acquiring the myelin-forming phenotype and that IF proteins of the neurofilament-type are not restricted to neurons in the vertebrate nervous system [7].
  • Schwann cells of the myelin-forming phenotype express neurofilament protein NF-M [7].
  • Immunological comparisons with other IF proteins revealed a close similarity between p145 and the neurofilament protein NF-M; the identification of p145 as NF-M was confirmed by isolating and sequencing a full-length clone from a Schwann cell cDNA library [7].
  • The cultured cells expressed two neuronal traits, tyrosine hydroxylase [L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating); EC] and the neuron-specific 160-kDa neurofilament subunit protein, but were devoid of glial fibrillary acidic protein, a marker for non-myelin-forming Schwann cells in ganglia [8].

Biological context of Nef3


Anatomical context of Nef3

  • Partial phosphorylation, denoted P[+], of NF-M was already present in perikarya and neurites of E12 neurons [13].
  • The results indicated that postnatal malnutrition imposed during the brain growth spurt period did not alter the expression of IF proteins of the cerebral cortex in 21-d-old rats, but increased the expression of NF-L and NF-M proteins in adult rats [14].
  • Left sciatic nerves were transected at postnatal day 3 (P3), 6 (P6), 8 (P8), or 10 (P10). mRNA and protein levels of the light (NF-L), mid-sized (NF-M), and heavy (NF-H) NF proteins were compared in L4 and L5 DRGs from the transected (left) vs. control (right) sides of the same animals at varying intervals after transection [15].
  • These findings suggest that the expression of the NF-M and NF-L polypeptides is an important characteristic of those Schwann cells that will contribute to the repair of damaged peripheral nerves [2].
  • The pellet contained the bulk of the cytoskeleton proteins from tissue, identified as the 150- and 68-kDa subunits of neurofilaments (NF-M and NF-L, respectively), the 66-kDa associated protein, the 57-kDa intermediate filament-like protein, and the 50-kDa glial fibrillary acidic protein [14].

Associations of Nef3 with chemical compounds

  • The molecule also contains an unusual C-terminal extension with stretches of glutamic acid, which could contribute to the anomalous migration of this protein on SDS-PAGE and the fact that NF-M does not readily assemble into filaments [9].
  • To demonstrate the site specificity of PKA phosphorylation and its effect on tail domain phosphorylation, we transfected NIH3T3 cells with NF-M mutated at PKA-specific head domain serine residues [10].
  • 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 [16].
  • 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 [17].
  • 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) [18].

Other interactions of Nef3


Analytical, diagnostic and therapeutic context of Nef3


  1. Monoclonal antibodies distinguish several differentially phosphorylated states of the two largest rat neurofilament subunits (NF-H and NF-M) and demonstrate their existence in the normal nervous system of adult rats. Lee, V.M., Carden, M.J., Schlaepfer, W.W., Trojanowski, J.Q. J. Neurosci. (1987) [Pubmed]
  2. 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]
  3. Cytoskeletal protein immunoexpression in fetal neural grafts: distribution of phosphorylated and nonphosphorylated neurofilament protein and microtubule-associated protein 2 (MAP-2). Rosenstein, J.M., Krum, J.M. Cell transplantation. (1996) [Pubmed]
  4. The differential role of protein kinase C isozymes in the rapid induction of neurofilament phosphorylation by nerve growth factor and phorbol esters in PC12 cells. Clark, E.A., Lee, V.M. J. Neurochem. (1991) [Pubmed]
  5. The Xenopus laevis homologue to the neuronal cyclin-dependent kinase (cdk5) is expressed in embryos by gastrulation. Gervasi, C., Szaro, B.G. Brain Res. Mol. Brain Res. (1995) [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. Schwann cells of the myelin-forming phenotype express neurofilament protein NF-M. Kelly, B.M., Gillespie, C.S., Sherman, D.L., Brophy, P.J. J. Cell Biol. (1992) [Pubmed]
  8. Insulin growth factors regulate the mitotic cycle in cultured rat sympathetic neuroblasts. DiCicco-Bloom, E., Black, I.B. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  9. Complete amino acid sequence and in vitro expression of rat NF-M, the middle molecular weight neurofilament protein. Napolitano, E.W., Chin, S.S., Colman, D.R., Liem, R.K. J. Neurosci. (1987) [Pubmed]
  10. Phosphorylation of the head domain of neurofilament protein (NF-M): a factor regulating topographic phosphorylation of NF-M tail domain KSP sites in neurons. Zheng, Y.L., Li, B.S., Veeranna, n.u.l.l., Pant, H.C. J. Biol. Chem. (2003) [Pubmed]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. Axonal dependency of the postnatal upregulation in neurofilament expression. Schwartz, M.L., Shneidman, P.S., Bruce, J., Schlaepfer, W.W. J. Neurosci. Res. (1990) [Pubmed]
  16. 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]
  17. 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]
  18. 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]
  19. Effects of acute and chronic administration of methylmalonic and propionic acids on the in vitro incorporation of 32P into cytoskeletal proteins from cerebral cortex of young rats. de Mattos-Dutra, A., de Freitas, M.S., Lisboa, C.S., Pessoa-Pureur, R., Wajner, M. Neurochem. Int. (1998) [Pubmed]
  20. Expression of rat neurofilament proteins NF-L and NF-M in transfected non-neuronal cells. Chin, S.S., Liem, R.K. Eur. J. Cell Biol. (1989) [Pubmed]
  21. Comprehensive immunofluorescence and lectin binding analysis of vibrissal follicle sinus complex innervation in the mystacial pad of the rat. Rice, F.L., Fundin, B.T., Arvidsson, J., Aldskogius, H., Johansson, O. J. Comp. Neurol. (1997) [Pubmed]
  22. Identification of novel in vitro PKA phosphorylation sites on the low and middle molecular mass neurofilament subunits by mass spectrometry. Cleverley, K.E., Betts, J.C., Blackstock, W.P., Gallo, J.M., Anderton, B.H. Biochemistry (1998) [Pubmed]
  23. Immunohistochemical studies on neurofilamentous hypertrophy in degenerating retinal terminals of the olivary pretectal nucleus in the rat. Meller, D., Schmidt-Kastner, R., Eysel, U.T. J. Comp. Neurol. (1993) [Pubmed]
  24. Acrylamide alters neurofilament protein gene expression in rat brain. Endo, H., Kittur, S., Sabri, M.I. Neurochem. Res. (1994) [Pubmed]
  25. Long-term effects of axotomy on beta-tubulin and NF gene expression in rat DRG neurons. Jiang, Y.Q., Pickett, J., Oblinger, M.M. Journal of neural transplantation & plasticity. (1994) [Pubmed]
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