The Differential Roles of Neurofilament Gene Expression and the Slowing of their Transport in the Radial Growth of Myelinated Axons

The axon's conduction velocity, and thus neuronal function, is dependent on the axonal cross-sectional area. The growth of axonal caliber is therefore a crucial developmental process. In mammals, most of the radial growth occurs after birth and is driven by an accumulation of neurofilaments (NFs), which are cytoskeletal protein polymers that serve a space-filling role in the cytoskeleton. NFs are synthesized in the cell body and transported into axons along microtubule (MT) tracks by molecular motor proteins. The NF accumulation is driven by an increase in the influx of NFs from the cell body and a decrease in their transport velocity within the axon. However, the relative contributions of these two mechanisms are unknown. To address this, we developed a computational model that is constrained by published data on cytoskeletal morphometry and NF transport kinetics to simulate the radial growth of axons in the ventral root and sciatic nerve of rats. Results show that early in postnatal development the radial growth of axons is driven primarily by an increase in the influx of NFs, but the slowing of NF transport becomes dominant later, indicating a possible metabolic advantage. We show that the slowing of NF transport can be explained by changes in the accessibility of the NFs for their MT tracks, which may be an important regulator of NF transport.