Trends in Cell Biology
Motor neurons rely on motor proteins
Section snippets
Kinesins
Initial observations in invertebrate models clearly showed the crucial role of kinesin during the development of the nervous system [3]. Although major defects in the organization of the neuromuscular system are not observed in Drosophila expressing mutations in kinesin heavy chain, at the cellular level axons develop marked swellings packed with vesicles, synaptic membrane proteins and mitochondria. Dystrophic neuromuscular junctions were also observed [4]. Mouse knockouts of two of the three
Interdependency of microtubule motors
Axonal transport is bidirectional, and accumulating evidence suggests that anterograde and retrograde motors function in an interdependent manner. Antibodies to either kinesin or dynactin result in a bidirectional inhibition of transport of vesicular motility in axoplasm in vitro 25, 26, 27. In Drosophila, dominant genetic interactions have been noted among kinesin, cytoplasmic dynein and dynactin [28]. We have observed a direct biochemical interaction between kinesin and cytoplasmic dynein
Transport defects linked to motor neuron degeneration
Although it is not surprising that microtubule motor proteins are required for the complex cytoskeletal changes occurring as neurons differentiate, migrate, extend growth cones and establish appropriate synaptic connections during development, the ongoing function of mature neurons is also dependent on active transport. This transport might be essential to maintain the health of all neurons but becomes particularly key in cells with extended axons such as those of the peripheral nervous system.
Is transport the Achilles' heal of the neuron?
If neurons are particularly dependent on axonal transport then both direct and indirect inhibition of this transport might be either causative or contributory factors to neurodegenerative disease. Although direct inhibition might be due to the types of motor mutations described above and summarized in Table 1, indirect effects might include the slowing of transport by protein aggregates or cytoskeletal disorder. For example, as described above, the accumulation of neurofilaments in the axon of
Concluding remarks and outstanding questions
Progress in understanding the mechanisms that drive axonal transport has been steady since the discovery of the intracellular microtubule motors kinesin and cytoplasmic dynein. These motors clearly play a role in the normal development of the nervous system, affecting neuronal migration, axonal pathfinding and synapse stabilization. However, studies of neurodegenerative diseases have highlighted the role of active axonal transport in maintaining the continued health of neuronal cells with
Acknowledgements
I thank Lee Ligon, Kevin K. Pfister, Karen Wallace, Mariko Tokito and David Howland for their intellectual input. I also thank Lee Ligon and the laboratories of Nobutaka Hirokawa, Larry Goldstein, Elizabeth Fisher and Gabriele Strumm for providing figures. My work was supported by a National Institutes of Health grant (GM48661) and the ALS Association.
References (60)
Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility
Cell
(1985)Kinesin heavy chain is essential for viability and neuromuscular functions in Drosophila, but mutants show no defects in mitosis
Cell
(1991)Targeted disruption of mouse conventional kinesin heavy chain, Kif5B, results in abnormal perinuclear clustering of mitochondria
Cell
(1998)- et al.
Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans
Cell
(1991) The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors
Cell
(1995)- et al.
Affinity chromatography demonstrates a direct binding between cytoplasmic dynein and the dynactin complex
J. Biol. Chem.
(1995) - et al.
Golgi and genetic mosaic analyses of visual system mutants in Drosophila melanogaster
Dev. Biol.
(1983) Dynein–dynactin function and sensory axon growth during Drosophila metamorphosis: a role for retrograde motors
Dev. Biol.
(1999)Dynactin is necessary for synapse stabilization
Neuron
(2002)- et al.
Mouse models of Charcot–Marie-Tooth disease
Trends Genet.
(2002)