期刊
JOURNAL OF CELL BIOLOGY
卷 163, 期 5, 页码 1021-1031出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200308076
关键词
NF-M phosphorylation; axonal transport; microtubules; ES cells; gene knockin
类别
资金
- NIA NIH HHS [AG0564] Funding Source: Medline
- NINDS NIH HHS [R01 NS027036, R01 NS 27036] Funding Source: Medline
T he 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-M-tailDelta) mutant mice using an embryonic stem cell-mediated gene knockin approach that preserves normal ratios of the three neurofilament subunits. Mutant NF-M-tailDelta 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.
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