INCREASING NEUROFILAMENT SUBUNIT NF-M EXPRESSION REDUCES AXONAL NF-H,INHIBITS RADIAL GROWTH, AND RESULTS IN NEUROFILAMENTOUS ACCUMULATION IN MOTOR-NEURONS

The carboxy-terminal tail domains of neurofilament subunits neurofilam ent NF-M and NF-H have been postulated to be responsible for the modul ation of axonal caliber. To test how subunit composition affects calib er, transgenic mice were generated to increase-axonal NF-M. Total neur ofilament subunit content in motor and sensory axons remained essentia lly unchanged, but increases in NF-M were offset by proportionate decr eases in both NF-H and axonal cross-sectional area. Increase in NF-M d id not affect the level of phosphorylation of NF-H. This indicates tha t (a) in vivo NF-H and NF-M compete either for coassembly with a limit ing amount of NF-L or as substrates for axonal transport, and (b) NF-H abundance is a primary determinant of axonal caliber. Despite inhibit ion of radial growth, increase in NF-M and reduction in axonal NF-H di d not affect nearest neighbor spacing between neurofilaments, indicati ng that cross-bridging between nearest neighbors does not play a cruci al role in radial growth. Increase in NF-M did not result in an overt phenotype or neuronal loss, although filamentous swellings in perikary a and proximal axons of motor neurons were frequently found.