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J. Cell Biol.,
Volume 143, Number 1, October 5, 1998 183-193
,'-Iminodipropionitrile
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 
,'-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.
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