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© The Rockefeller University Press, 0021-9525/1998//183 $5.00
The Journal of Cell Biology, Volume 143, Number 1, , 1998 183-193

Regular Articles

Disruption of the NF-H Gene Increases Axonal Microtubule Content and Velocity of Neurofilament Transport: Relief of Axonopathy Resulting from the Toxin β,β'-Iminodipropionitrile



Qinzhang Zhu, Michael Lindenbaum, Françoise Levavasseur, Hélène Jacomy, and Jean-Pierre Julien

Centre for Research in Neuroscience, McGill University, The Montreal General Hospital Research Institute, Montréal, Qúebec, Canada H3G 1A4

To investigate the role of the neurofilament heavy (NF-H) subunit in neuronal function, we generated mice bearing a targeted disruption of the gene coding for the NF-H subunit. Surprisingly, the lack of NF-H subunits had little effect on axonal calibers and electron microscopy revealed no significant changes in the number and packing density of neurofilaments made up of only the neurofilament light (NF-L) and neurofilament medium (NF-M) subunits. However, our analysis of NF-H knockout mice revealed an ~2.4-fold increase of microtubule density in their large ventral root axons. This finding was further corroborated by a corresponding increase in the ratio of assembled tubulin to NF-L protein in insoluble cytoskeletal preparations from the sciatic nerve. Axonal transport studies carried out by the injection of [35S]methionine into spinal cord revealed an increased transport velocity of newly synthesized NF-L and NF-M proteins in motor axons of NF-H knockout mice. When treated with β,β'-iminodipropionitrile (IDPN), a neurotoxin that segregates microtubules and retards neurofilament transport, mice heterozygous or homozygous for the NF-H null mutation did not develop neurofilamentous swellings in motor neurons, unlike normal mouse littermates. These results indicate that the NF-H subunit is a key mediator of IDPN-induced axonopathy.

Key Words: neurofilament • axon caliber • microtubules • iminodipropionitrile • gene targeting

Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; DRG, dorsal root ganglia; ES, embryonic stem; IDPN, β,β'-iminodipropionitrile; NF-H/NF-L/NF-M, neurofilament heavy/neurofilament light/ neurofilament medium.

The technical assistance of P. Hince, D. Altshuller, D. Houle, and G. Gagnon is gratefully acknowledged.

Address all correspondence to Jean-Pierre Julien, The Montreal General Hospital Research Institute, 1650 Cedar Avenue, Montréal, Québec, Canada H3G 1A4. Tel.: (514) 937-6011 ext. 2361. Fax: (514) 934-8265. E-mail: mdju{at}musica.mcgill.ca


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