Neuronal Growth and Death: Order and Disorder in the Axoplasm

no neurofilaments in axons as a consequence of premature translation termination in NF-L (Ohara et al., 1993). Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience This results in no detectable NF-L protein, total absence of neurofilaments, and resultant axons that almost com-University of California, San Diego 9500 Gilman Drive pletely fail to grow radially. A central limit to neurofilment-dependent radial La Jolla, California 92093 growth is the velocity and quantity of components delivered to axons by axonal transport. Transport is a necessity for neurons, as protein synthesis is restricted to Neurons, whose long thin axonal processes represent cell bodies and dendrites. Membrane-bound particles the conduits for electrical signaling, are the most asym-in axons are trafficked rapidly in both directions using metric cells in nature. Asymmetry arises in two steps, ATP-dependent microtubule motors. The remaining each mediated by different cytoskeletal elements. Initial components, including all known cytoskeletal proteins, neurite elongation utilizes actin/myosin for growth cone locomotion and microtubules as tracks along which proteins and membranes are delivered from the cell body toward the developing axon terminus. After a stable synapse has formed, a second phase, termed radial growth, is initiated during which neurofilaments, the intermediate filaments of most large neurons, accumulate to become the most abundant cytoskeletal elements (Figure 1B) and the axonal diameters increase by up to an order of magnitude (leading to up to a 100-fold increase in volume!). Radial growth initially occurs rapidly, concomitant with myelination, and then continues slowly throughout adulthood. This is important to neu-ronal function since diameter represents one of the two key determinants specifying velocity of electrical signal conduction, the other being the amount of insulation provided by myelin. For the meter-long human motor and sensory neurons of the peripheral nervous system, the initial elongation phase yields a cell >10 4 times longer than most animal cells, while radial growth yields a cell volume 10 3 times bigger than is typical and >99.9% of which is in the axon (see Figure 1A). These properties highlight a key general question in cell biology: what are the principles specifying cell volume and how does a structural scaffolding, such as an array of neurofilaments (Figure 1B), determine and maintain cell (or in the present examples, axo-nal) volume? What I attempt here is review of what is known about how neurofilaments mediate radial growth and how aberrations in filament organization can be direct causes of …