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Gene Review

Nefl  -  neurofilament, light polypeptide

Mus musculus

Synonyms: 68 kDa neurofilament protein, AI847934, CMT2E, NF-L, NF68, ...
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Disease relevance of Nefl

  • Depletion of the Nefl gene in mice mimicks the reduced NFL mRNA levels seen in amyotrophic lateral sclerosis and causes perikaryal accumulation of neurofilament proteins and axonal hypotrophy in motoneurons [1].
  • By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced [2].
  • When the NF-L coding region was linked to the strong promoter from Moloney Murine Sarcoma virus, we obtained high levels of synthesis of NF-L subunits (accumulating to as much as 9% of cell protein in stable cell lines) [3].
  • Knockdown of NUDEL by RNA interference (RNAi) in a neuroblastoma cell line, primary cortical neurons or post-natal mouse brain destabilizes NF-L and alters the homeostasis of NFs [4].
  • These results indicate that, as early as 6 months, depletion of the NFL protein is sufficient to cause mild sensorimotor dysfunctions and spatial deficits, but without overt signs of paresis [5].

Psychiatry related information on Nefl

  • Mice with a null mutation of the Nefl gene were compared with normal controls in tests of motor activity, equilibrium, and spatial orientation [5].

High impact information on Nefl

  • Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease [6].
  • To test directly the consequence of overexpression of the major neurofilament subunit NF-L, we produced transgenic mice that accumulate NF-L to approximately 4-fold the normal level in the sciatic nerve [6].
  • NF-L accumulation is accompanied by an increased frequency of axonal degeneration, proximal axon swelling, and severe skeletal muscle atrophy [6].
  • To investigate the regulation of neurofilament gene expression, we have generated several lines of transgenic mice carrying multiple copies of a cloned human neurofilament (NF-L) gene [7].
  • NUDEL facilitates the polymerization of NFs through a direct interaction with the NF light subunit (NF-L) [4].

Biological context of Nefl

  • To further investigate the toxic properties of IF protein inclusions, we generated NF-L null mice that co-express both peripherin and NF-H transgenes [8].
  • In addition, axonal transport studies carried out by the injection of [35S]methionine into spinal cord revealed after 30 days very low levels of newly synthesized NF-L proteins in the sciatic nerve of NF-M-/-;NF-H-/- mice [9].
  • The coding sequence is interrupted by two intervening sequences which align perfectly with the first two intervening sequences in the gene encoding NF-L (the low-molecular-mass neurofilament protein); there is no intron in the gene encoding NF-M corresponding to the third intron in NF-L [10].
  • Screening of a lambda gt10 cDNA library prepared from mouse brain RNA led to the cloning of an NF-L cDNA of 2.0 kb that spans the entire coding region of 541 amino acids and of an NF-M cDNA that covers 219 amino acids from the internal alpha-helical region and the carboxy-terminal domains of the protein [11].
  • The light (NF-L), mid-sized (NF-M) and heavy (NF-H) neurofilament (NF) genes were probed with methylation-sensitive restriction enzymes and patterns of methylation and expression of the NF genes were compared in tissues and cell lines of the mouse [12].

Anatomical context of Nefl

  • The combined results demonstrate a requirement of the high-molecular-weight subunits for the assembly of type IV intermediate filament proteins and for the efficient translocation of NF-L proteins into the axonal compartment [9].
  • The NFL null mice displayed enzymatic activity alterations in numerous hindbrain regions, mainly the cerebellum, connected regions of the brainstem (red nucleus, vestibular nuclei, and reticular formation), and cranial nerve nuclei [1].
  • At this age, NF-L and NF-M are detected primarily in the processes of horizontal cells and retinal ganglion cells, but are rarely found in amacrine cell processes [13].
  • In vivo pulse radiolabeling analyses in retinal ganglion cell neurons revealed that NF-L alone is incapable of efficient transport, whereas nearly one-half of the normal level of NF-M is transported along optic axons in the absence of the other triplet subunits [14].
  • NF-L was preferentially localized to perikarya and proximal neurites; NF-M[P++] and NF-H[P ] were distributed to distal aspects of neurites [15].

Associations of Nefl with chemical compounds

  • Hence, the two end domains of NF-L have antagonistic effects on the lateral association of protofilaments into higher-order structures, with the effect of the COOH-terminal tail domain being dominant over that of the NH2-terminal head domain [16].
  • Immunoelectron microscopy investigations of the incorporation sites of NF-H labeled with biotin compounds also revealed the lateral insertion of NF-H subunits into the preexisting NF array, taking after the pattern seen in the case of NF-L [17].
  • However, both cyclosporin A and FK506 treatments affected neither NF-L gene expression nor neurite outgrowth [18].
  • The turnover of phosphate groups on NF-L during axonal transport was determined after the neurofilaments in retinal ganglion cells were phosphorylated in vivo by injecting mice intravitreally with [32P]orthophosphate [19].
  • Instead, the mutant assembled efficiently in buffers containing CaCl2 > or = 6 mM forming filaments that were 10 times longer than those formed by wt NF-L, although their diameter was significantly smaller (6-7 nm) [20].

Physical interactions of Nefl

  • In addition, retardation in morphological transformation from activated to amoeboid microglia in response to sciatic nerve injury, differential expressions of some cytokines in the lumbar cord segments and induction of Iba-1 (ionized calcium-binding adaptor molecule-1) expression in microglia were observed in NFL-/- mice [21].
  • These results demonstrate that the OA treatment inhibits the differentiation-dependent increase in NF-L gene expression by destabilizing its mRNAs and suggest that PP2A plays key roles in the differentiation-dependent enhanced expression of the NF-L gene and is the point of the action of OA [18].
  • A similar but more severe phenotype was observed when the chimeric transgene contained a 36 bp c-myc insert in an mRNA destabilizing element of the NF-L sequence [22].

Regulatory relationships of Nefl

  • The expression and activity levels of protein phosphatase 2A (PP2A) and 2B (PP2B) but not protein phosphatase 1 (PP1) in P19 cells increased in accordance with the enhanced NF-L gene expression [18].
  • In this study, we demonstrated that the neurofilament-L (NF-L) mRNA and protein levels of these cells were enhanced in accordance with their retinoic acid-induced neural differentiation [18].
  • Moreover, addition of H-ras protein enhances the survival of Nfl(-/-), but not wild-type, DRG neurons [23].

Other interactions of Nefl

  • These studies suggest that the NF-M subunit is a major regulator of the level of NF-L and that its presence is required to achieve maximal axonal diameter in all size classes of myelinated axons [24].
  • Immunoelectron microscopy, coimmunoprecipitation, and blot overlay analyses demonstrate that myosin Va in axons associates with neurofilaments, and that the NF-L subunit is its major ligand [25].
  • NF-L and NF-H expression appeared later, by day E16.5, and was weak for the entire pre- and postnatal life [26].
  • Protein analysis indicated that the levels of NF-L and alpha-internexin proteins were reduced dramatically throughout the nervous system [9].
  • Remarkably, the onset of peripherin-mediated disease was precipitated by a deficiency of neurofilament light (NF-L) protein, a phenomenon associated with sporadic ALS [27].

Analytical, diagnostic and therapeutic context of Nefl


  1. Mice with the deleted neurofilament of low-molecular-weight (Nefl) gene: 1. Effects on regional brain metabolism. Dubois, M., Lalonde, R., Julien, J.P., Strazielle, C. J. Neurosci. Res. (2005) [Pubmed]
  2. Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. Williamson, T.L., Bruijn, L.I., Zhu, Q., Anderson, K.L., Anderson, S.D., Julien, J.P., Cleveland, D.W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  3. Expression of NF-L and NF-M in fibroblasts reveals coassembly of neurofilament and vimentin subunits. Monteiro, M.J., Cleveland, D.W. J. Cell Biol. (1989) [Pubmed]
  4. A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons. Nguyen, M.D., Shu, T., Sanada, K., Larivière, R.C., Tseng, H.C., Park, S.K., Julien, J.P., Tsai, L.H. Nat. Cell Biol. (2004) [Pubmed]
  5. Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation. Dubois, M., Strazielle, C., Julien, J.P., Lalonde, R. J. Neurosci. Res. (2005) [Pubmed]
  6. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Xu, Z., Cork, L.C., Griffin, J.W., Cleveland, D.W. Cell (1993) [Pubmed]
  7. Expression and assembly of a human neurofilament protein in transgenic mice provide a novel neuronal marking system. Julien, J.P., Tretjakoff, I., Beaudet, L., Peterson, A. Genes Dev. (1987) [Pubmed]
  8. Peripherin-mediated death of motor neurons rescued by overexpression of neurofilament NF-H proteins. Beaulieu, J.M., Julien, J.P. J. Neurochem. (2003) [Pubmed]
  9. Disruption of type IV intermediate filament network in mice lacking the neurofilament medium and heavy subunits. Jacomy, H., Zhu, Q., Couillard-Després, S., Beaulieu, J.M., Julien, J.P. J. Neurochem. (1999) [Pubmed]
  10. Structure and evolutionary origin of the gene encoding mouse NF-M, the middle-molecular-mass neurofilament protein. Levy, E., Liem, R.K., D'Eustachio, P., Cowan, N.J. Eur. J. Biochem. (1987) [Pubmed]
  11. Cloning and developmental expression of the murine neurofilament gene family. Julien, J.P., Meyer, D., Flavell, D., Hurst, J., Grosveld, F. Brain Res. (1986) [Pubmed]
  12. Methylation and expression of neurofilament genes in tissues and in cell lines of the mouse. Bruce, J., Schwartz, M.L., Shneidman, P.S., Schlaepfer, W.W. Brain Res. Mol. Brain Res. (1993) [Pubmed]
  13. The neuronal intermediate filament, alpha-internexin is transiently expressed in amacrine cells in the developing mouse retina. Chien, C.L., Liem, R.K. Exp. Eye Res. (1995) [Pubmed]
  14. Neurofilament transport in vivo minimally requires hetero-oligomer formation. Yuan, A., Rao, M.V., Kumar, A., Julien, J.P., Nixon, R.A. J. Neurosci. (2003) [Pubmed]
  15. Constitutive expression of the mature array of neurofilament proteins by a CNS neuronal cell line. Lee, H.J., Elliot, G.J., Hammond, D.N., Lee, V.M., Wainer, B.H. Brain Res. (1991) [Pubmed]
  16. The rod domain of NF-L determines neurofilament architecture, whereas the end domains specify filament assembly and network formation. Heins, S., Wong, P.C., Müller, S., Goldie, K., Cleveland, D.W., Aebi, U. J. Cell Biol. (1993) [Pubmed]
  17. Differential dynamics of neurofilament-H protein and neurofilament-L protein in neurons. Takeda, S., Okabe, S., Funakoshi, T., Hirokawa, N. J. Cell Biol. (1994) [Pubmed]
  18. Okadaic acid suppresses neural differentiation-dependent expression of the neurofilament-L gene in P19 embryonal carcinoma cells by post-transcriptional modification. Sasahara, Y., Kobayashi, T., Onodera, H., Onoda, M., Ohnishi, M., Kato, S., Kusuda, K., Shima, H., Nagao, M., Abe, H., Yanagawa, Y., Hiraga, A., Tamura, S. J. Biol. Chem. (1996) [Pubmed]
  19. Identification of Ser-55 as a major protein kinase A phosphorylation site on the 70-kDa subunit of neurofilaments. Early turnover during axonal transport. Sihag, R.K., Nixon, R.A. J. Biol. Chem. (1991) [Pubmed]
  20. In vitro assembly properties of mutant and chimeric intermediate filament proteins: insight into the function of sequences in the rod and end domains of IF. Gu, L., Troncoso, J.C., Wade, J.B., Monteiro, M.J. Exp. Cell Res. (2004) [Pubmed]
  21. Mice with targeted disruption of neurofilament light subunit display formation of protein aggregation in motoneurons and downregulation of complement receptor type 3 alpha subunit in microglia in the spinal cord at their earlier age: A possible feature in pre-clinical development of neurodegenerative diseases. Li, Z.H., Lu, J., Tay, S.S., Wu, Y.J., Strong, M.J., He, B.P. Brain Res. (2006) [Pubmed]
  22. Untranslated element in neurofilament mRNA has neuropathic effect on motor neurons of transgenic mice. Nie, Z., Wu, J., Zhai, J., Lin, H., Ge, W., Schlaepfer, W.W., Cañete-Soler, R. J. Neurosci. (2002) [Pubmed]
  23. Neurofibromin negatively regulates neurotrophin signaling through p21ras in embryonic sensory neurons. Vogel, K.S., El-Afandi, M., Parada, L.F. Mol. Cell. Neurosci. (2000) [Pubmed]
  24. Absence of the mid-sized neurofilament subunit decreases axonal calibers, levels of light neurofilament (NF-L), and neurofilament content. Elder, G.A., Friedrich, V.L., Bosco, P., Kang, C., Gourov, A., Tu, P.H., Lee, V.M., Lazzarini, R.A. J. Cell Biol. (1998) [Pubmed]
  25. Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density. Rao, M.V., Engle, L.J., Mohan, P.S., Yuan, A., Qiu, D., Cataldo, A., Hassinger, L., Jacobsen, S., Lee, V.M., Andreadis, A., Julien, J.P., Bridgman, P.C., Nixon, R.A. J. Cell Biol. (2002) [Pubmed]
  26. The cytoskeleton of the myenteric neurons during murine embryonic life. Faussone-Pellegrini, M.S., Matini, P., DeFelici, M. Anat. Embryol. (1999) [Pubmed]
  27. Late onset of motor neurons in mice overexpressing wild-type peripherin. Beaulieu, J.M., Nguyen, M.D., Julien, J.P. J. Cell Biol. (1999) [Pubmed]
  28. Structure of the 68-kDa neurofilament gene and regulation of its expression. Nakahira, K., Ikenaka, K., Wada, K., Tamura, T., Furuichi, T., Mikoshiba, K. J. Biol. Chem. (1990) [Pubmed]
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