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© The Rockefeller University Press, 0021-9525/1998//195 $5.00
The Journal of Cell Biology, Volume 143, Number 1, , 1998 195-205

Regular Articles

Requirement of Heavy Neurofilament Subunit in the Development of Axons with Large Calibers



Gregory A. Elder*, Victor L. Friedrich, Jr.{ddagger}, Chulho Kang{ddagger}, Paolo Bosco{ddagger}, Andrei Gourov*, Pang-Hsien Tu§, Bin Zhang§, Virginia M.-Y. Lee§, and Robert A. Lazzarini{ddagger}

* Department of Psychiatry, {ddagger} Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029; and § Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Neurofilaments (NFs) are prominent components of large myelinated axons. Previous studies have suggested that NF number as well as the phosphorylation state of the COOH-terminal tail of the heavy neurofilament (NF-H) subunit are major determinants of axonal caliber. We created NF-H knockout mice to assess the contribution of NF-H to the development of axon size as well as its effect on the amounts of low and mid-sized NF subunits (NF-L and NF-M respectively). Surprisingly, we found that NF-L levels were reduced only slightly whereas NF-M and tubulin proteins were unchanged in NF-H–null mice. However, the calibers of both large and small diameter myelinated axons were diminished in NF-H–null mice despite the fact that these mice showed only a slight decrease in NF density and that filaments in the mutant were most frequently spaced at the same interfilament distance found in control. Significantly, large diameter axons failed to develop in both the central and peripheral nervous systems. These results demonstrate directly that unlike losing the NF-L or NF-M subunits, loss of NF-H has only a slight effect on NF number in axons. Yet NF-H plays a major role in the development of large diameter axons.

Key Words: neurofilament proteins • neuronal cytoskeleton • mice • knockout • gene targeting • large diameter axons

Abbreviations used in this paper: CNS, central nervous system; ES, embryonic stem; IF, intermediate filament; neo, neomycin; NF, neurofilament; NF-H, heavy neurofilament; NF-L, light neurofilament; NF-M, mid-sized neurofilament; PGK-1, phosphoglycerol kinase-1; PNS, peripheral nervous system.

Address all correspondence to R.A. Lazzarini, Brookdale Center for Developmental and Molecular Biology, Box 1126, Mount Sinai School of Medicine, New York, NY 10029. Tel.: (212) 241-4272. Fax: (212) 860-9279. E-mail: rlazzar{at}smtplink.mssm.edu


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