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Published 8 December 2003. doi:10.1083/jcb.200308076
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© The Rockefeller University Press, 0021-9525/2003/12/1021 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 1021-1031

Article

 The neurofilament middle molecular mass subunit carboxyl-terminal tail domains is essential for the radial growth and cytoskeletal architecture of axons but not for regulating neurofilament transport rate

Mala V. Rao1,2, Jabbar Campbell1, Aidong Yuan1,2, Asok Kumar1,4, Takahiro Gotow5, Yasuo Uchiyama6 and Ralph A. Nixon1,2,3

1 Nathan Kline Institute, New York University (NYU) School of Medicine, Orangeburg, NY 10962
2 Department of Psychiatry, NYU School of Medicine, New York, NY 10016
3 Department of Cell Biology, NYU School of Medicine, New York, NY 10016
4 Department of Pathology, NYU School of Medicine, New York, NY 10016
5 Laboratory of Cell Biology, College of Nutrition, Koshien University, Takarazuka, Hyogo 665-0006, Japan
6 Department of Cell Biology and Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

Address correspondence to Mala V. Rao, Nathan Kline Institute, NYU School of Medicine, 140 Old Orangeburg Rd., Orangeburg, NY 10962. Tel.: (845) 398-5547. Fax: (845) 398-5422. email: rao{at}nki.rfmh.org

The phosphorylated carboxyl-terminal "tail" domains of the neurofilament (NF) subunits, NF heavy (NF-H) and NF medium (NF-M) subunits, have been proposed to regulate axon radial growth, neurofilament spacing, and neurofilament transport rate, but direct in vivo evidence is lacking. Because deletion of the tail domain of NF-H did not alter these axonal properties (Rao, M.V., M.L. Garcia, Y. Miyazaki, T. Gotow, A. Yuan, S. Mattina, C.M. Ward, N.S. Calcutt, Y. Uchiyama, R.A. Nixon, and D.W. Cleveland. 2002. J. Cell Biol. 158:681–693), we investigated possible functions of the NF-M tail domain by constructing NF-M tail–deleted (NF-Mtail{Delta}) mutant mice using an embryonic stem cell–mediated "gene knockin" approach that preserves normal ratios of the three neurofilament subunits. Mutant NF-Mtail{Delta} mice exhibited severely inhibited radial growth of both motor and sensory axons. Caliber reduction was accompanied by reduced spacing between neurofilaments and loss of long cross-bridges with no change in neurofilament protein content. These observations define distinctive functions of the NF-M tail in regulating axon caliber by modulating the organization of the neurofilament network within axons. Surprisingly, the average rate of axonal transport of neurofilaments was unaltered despite these substantial effects on axon morphology. These results demonstrate that NF-M tail–mediated interactions of neurofilaments, independent of NF transport rate, are critical determinants of the size and cytoskeletal architecture of axons, and are mediated, in part, by the highly phosphorylated tail domain of NF-M.

Key Words: NF-M phosphorylation; axonal transport; microtubules; ES cells; gene knockin

Abbreviations used in this paper: NF, neurofilament; NF-H, NF heavy subunit; NF-L, NF light subunit; NF-M, NF medium subunit.


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