Axonal neurofilaments are closely packed in mice lacking the phosphorylated NF-M tail (bottom).

Axons are fattened by an unexpected neurofilament (NF) subunit, according to Garcia et al. (page 1011) and Rao et al. (page 1021), who find that more phosphorylation sites are not necessarily better when it comes to driving axon expansion.

The radial growth-inducing subunit is one of three that make up NFs. The COOH-terminal tails of two of these subunits, NF-H and NF-M, extend perpendicular to the main NF axis and thus bridge NFs with adjacent NFs, actin filaments, or microtubules. These COOH-terminal tails are phosphorylated in response to myelination, which also initiates a tenfold expansion in volume that is critical for fast conduction of action potentials. As NF-H has 51 phosphorylation sites in its COOH- terminal tail, and NF-M has just 7, NF-H was assumed to be the key phosphorylation target in axonal expansion, with some researchers suggesting that repulsion between all these negatively charged groups was driving expansion. But both groups find that NF-M, but not NF-H, is the driving force.

The articles report on mice lacking the phosphorylatable NF tails. All of the mice had normal NF levels, but axons only expanded in mice that contained phosphorylated NF-M bridges. Axon filaments in the NF-M mutants were thus more closely packed. NF-M phosphorylation may be required for the binding of interlinking proteins, such as plakins, which then force expansion by pushing apart the filaments. NF-H tail deletions did not have the same effects—axons grew to normal size despite lacking the long NF-H cross-bridges—so the function of NF-H phosphorylation is still a mystery.

In the smaller axons of the NF-M mutants, action potentials were conducted at two-thirds the normal rate, although the mice developed and acted normally. Larger animals, however, whose nerves must transmit impulses greater distances, display neurological disorders when conduction velocities are impaired. Perhaps NF-M phosphorylation is impaired in human disorders such as Charcot-Marie-Tooth disease, in which reduced myelination slows nervous impulses. ▪