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

Abstract

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.

Cdk5 regulates axonal transport and phosphorylation of neurofilaments in cultured neurons

“…Moreover, in mice in which either the entire NF-H molecule or its sidearm has been delected, NF-M sidearm phosphorylation undergoes a compensatory increase to the extent that it displays the phosphorylation-dependent developmentally delayed phospho-epitopes, which are usually only detected on NF-H (Rao et al, 2002;Sanchez et al, 2000;Tu et al, 1995;Zhu et al, 1998). Such compensatory changes in NF-M after modulation of NFH expression might affect NF transport following the deletion of NF-H and /or the NF-H sidearm.…”

Neurofilaments at a glance

“…Phosphorylation of the tail domain is specific for particular regions within the cell, with non-phosphorylated tails predominately found in the cell bodies, which become highly phosphorylated in mature axons (see poster panel Modification of neurofilaments: NF head phosphorylation, Tail phosphorylation). This developmentally regulated phosphorylation appears to depend on myelination and synaptogenesis Sánchez et al, 2000). Although the dendrites also harbor NFs, these filaments are, for unknown reasons, not highly phosphorylated Sternberger and Sternberger, 1983).…”

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy

“…As axonal caliber is a major determinant of conduction velocity, the capacity of SHh-IgG to restore or maintain the proportion of large myelinated fibers in the sciatic nerve of diabetic rats reveals a potential mechanism that could explain the effect of SHh-IgG on conduction. Radial growth of axons and maintenance of axonal caliber is determined by neurofilament proteins and their phosphorylation status (31)(32)(33)(34). Defects in neurofilament gene expression, synthesis, axonal transport, and phosphorylation have all been implicated in the decreased axonal caliber seen in diabetic rodents (19,(35)(36)(37).…”