Abstract
Regulation of microtubule dynamics underlies many fundamental cellular mechanisms including cell division, cell motility, and transport. In neurons, microtubules play key roles in cell migration, axon outgrowth, control of axon and synapse growth, and the regulated transport of vesicles and structural components of synapses. Loss of synapse and axon integrity and disruption of axon transport characterize many neurodegenerative diseases. Recently, mutations that specifically alter the assembly or stability of microtubules have been found to directly cause neurodevelopmental defects or neurodegeneration in vertebrates. We report here the characterization of a missense mutation in the C-terminal domain of C. elegans alpha-tubulin, tba-1(ju89), that disrupts motor neuron synapse and axon development. Mutant ju89 animals exhibit reduction in the number and size of neuromuscular synapses, altered locomotion, and defects in axon extension. Although null mutations of tba-1 show a nearly wild-type pattern, similar axon outgrowth defects were observed in animals lacking the beta-tubulin TBB-2. Genetic analysis reveals that tba-1(ju89) affects synapse development independent of its role in axon outgrowth. tba-1(ju89) is an altered function allele that most likely perturbs interactions between TBA-1 and specific microtubule-associated proteins that control microtubule dynamics and transport of components needed for synapse and axon growth.
Highlights
Microtubules play multiple essential roles in cells including forming the mitotic spindle, transporting vesicles and organelles, providing structural support as part of the cytoskeleton, and serving as platforms for the assembly of signaling complexes
To determine if the decreased number of GABAergic synapses in ju89 mutants was due solely to defects in initial axon outgrowth and extension along the nerve cords, we examined the morphology of the dorsal D (DD) motor neurons in more detail
When we examined deletion alleles of tba-1, tbb-1 and tbb-2 generated by the C. elegans Gene Knock-out Consortium for Figure 5. ju89 is a Novel Allele of C. elegans Alpha-Tubulin tba-1. (A) location of ju89 on C. elegans chromosome I based on genetic map data, (B) Transformation rescue of ju89 by F24E4.8
Summary
Microtubules play multiple essential roles in cells including forming the mitotic spindle, transporting vesicles and organelles, providing structural support as part of the cytoskeleton, and serving as platforms for the assembly of signaling complexes. Microtubules are dynamic polymers, and their assembly and disassembly is highly regulated. Misregulation of microtubules, loss of synapses and breakdown of transport mechanisms have long been recognized as common denominators in the pathology of neurodegenerative diseases. The presence of hyper-phosphorylated tau in the neurofibrillary tangles of Alzheimer’s patients is one of the most intensely studied examples, but an increasing number of studies have established that perturbing any of the major mechanisms that regulate microtubule dynamics and transport can impact neural development or contribute to neuronal disease. Examples include mutations in tubulin folding co-factor E [7], the dynactin complex [8,9] and the microtubule severing protein, spastin [10], which have all been implicated in motor neuron degeneration
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