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© The Rockefeller University Press, 0021-9525/2000//1013 $5.00
The Journal of Cell Biology, Volume 151, Number 5, , 2000 1013-1024

Local Control of Neurofilament Accumulation during Radial Growth of Myelinating Axons in Vivo

Ivelisse Sánchez^a,c, Linda Hassinger^c, Ram K. Sihag^c, Don W. Cleveland^d, Panaiyur Mohan^c, and Ralph A. Nixon^a,c,b

^a Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115
^b Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115
^c Laboratories for Molecular Neuroscience, McLean Hospital, Belmont, Massachusetts
^d Ludwig Cancer Institute at University of California at San Diego, La Jolla, California 92093

The accumulation of neurofilaments required for postnatal radial growth of myelinated axons is controlled regionally along axons by oligodendroglia. Developmentally regulated processes previously suspected of modulating neurofilament number, including heavy neurofilament subunit (NFH) expression, attainment of mature neurofilament subunit stoichiometry, and expansion of interneurofilament spacing cannot be primary determinants of regional accumulation as we show each of these factors precede accumulation by days or weeks. Rather, we find that regional neurofilament accumulation is selectively associated with phosphorylation of a subset of Lys-Ser-Pro (KSP) motifs on heavy neurofilament subunits and medium-size neurofilament subunits (NFMs), rising >50-fold selectively in the expanding portions of optic axons. In mice deleted in NFH, substantial preservation of regional neurofilament accumulation was accompanied by increased levels of the same phosphorylated KSP epitope on NFM. Interruption of oligodendroglial signaling to axons in Shiverer mutant mice, which selectively inhibited this site-specific phosphorylation, reduced regional neurofilament accumulation without affecting other neurofilament properties or aspects of NFH phosphorylation. We conclude that phosphorylation of a specific KSP motif triggered by glia is a key aspect of the regulation of neurofilament number in axons during axonal radial growth.

Key Words: axon caliber • axon–glia interactions • oligodendroglia • CNS development • protein phosphorylation

© 2000 The Rockefeller University Press

R.K. Sihag's present address is Laboratory of Neurobiology, Bldg. 36 Rm. 2A-21, NINDS/NIH, 9000 Rockville Pike, Bethesda, MD 20892-4062.

P. Mohan's present address is Nathan Kline Institute for Psychiatric Research, New York University School of Medicine, 140 Old Orangeburg Rd., Orangeburg, NY 10962.

Abbreviations used in this paper: CNS, central nervous system; ddw, double distilled water; ERK, extracellular signal–regulated kinase; KSP, Lys-Ser-Pro; MBP, myelin basic protein; NFH, heavy neurofilament subunit; NFL, light neurofilament subunit; NFM, medium-size neurofilament subunit; RGC, retinal ganglion cell; TBS, Tris-buffered saline.

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