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The Journal of Neuroscience, February 4, 2009, 29(5):1277-1284; doi:10.1523/JNEUROSCI.3765-08.2009

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Cellular/Molecular
Phosphorylation of Highly Conserved Neurofilament Medium KSP Repeats Is Not Required for Myelin-Dependent Radial Axonal Growth

Michael L. Garcia,^1,2 Mala V. Rao,^6,7 Jiro Fujimoto,² Virginia B. Garcia,¹ Sameer B. Shah,⁸ John Crum,⁴ Takahiro Gotow,⁹ Yasuo Uchiyama,¹⁰ Mark Ellisman,^3,4 Nigel A. Calcutt,⁵ and Don W. Cleveland^2,3

¹Department of Biological Sciences, Bond Life Sciences Center, University of Missouri–Columbia, Columbia, Missouri 65211, ²Ludwig Institute for Cancer Research, ³Department of Neurosciences, ⁴National Center for Microscopy and Image Research, and ⁵Department of Pathology, University of California, San Diego, La Jolla, California 92093, ⁶Nathan Kline Institute, ⁷Department of Psychiatry, New York University School of Medicine, Orangeburg, New York 10962, ⁸Fischell Department of Bioengineering, University of Maryland, College Park, Maryland 20742, ⁹Laboratory of Cell Biology, College of Nutrition, Koshien University, Hyogo 665-0006, Japan, and ¹⁰Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan

Correspondence should be addressed to Dr. Don W. Cleveland, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92903. Email: dcleveland{at}ucsd.edu

Neurofilament medium (NF-M) is essential for the acquisition of normal axonal caliber in response to a myelin-dependent "outside-in" trigger for radial axonal growth. Removal of the tail domain and lysine-serine-proline (KSP) repeats of NF-M, but not neurofilament heavy, produced axons with impaired radial growth and reduced conduction velocities. These earlier findings supported myelin-dependent phosphorylation of NF-M KSP repeats as an essential component of axonal growth. As a direct test of whether phosphorylation of NF-M KSP repeats is the target for the myelin-derived signal, gene replacement has now been used to produce mice in which all serines of NF-M's KSP repeats have been replaced with phosphorylation-incompetent alanines. This substitution did not alter accumulation of the neurofilaments or their subunits. Axonal caliber and motor neuron conduction velocity of mice expressing KSP phospho-incompetent NF-M were also indistinguishable from wild-type mice. Thus, phosphorylation of NF-M KSP repeats is not an essential component for the acquisition of normal axonal caliber mediated by myelin-dependent outside-in signaling.

Key words: neurofilaments; cytoskeleton; myelination; radial growth; motor neuron; phosphorylation

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Received Aug. 9, 2008; revised Dec. 22, 2008; accepted Dec. 29, 2008.

Correspondence should be addressed to Dr. Don W. Cleveland, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92903. Email: dcleveland{at}ucsd.edu

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