Abstract
Microtubule plus‐end directed trafficking is dominated by kinesin motors, yet kinesins differ in terms of cargo identity, movement rate, and distance travelled. Functional diversity of kinesins is especially apparent in polarized neurons, where long distance trafficking is required for efficient signal transduction‐behavioral response paradigms. The Kinesin‐3 superfamily are expressed in neurons and are hypothesized to have significant roles in neuronal signal transduction due to their high processivity. Although much is known about Kinesin‐3 motors mechanistically in vitro, there is little known about their mechanisms in vivo. Here, we analyzed KLP‐4, the Caenorhabditis elegans homologue of human KIF13A and KIF13B. Like other Kinesin‐3 superfamily motors, klp‐4 is highly expressed in the ventral nerve cord command interneurons of the animal, suggesting it might have a role in controlling movement of the animal. We characterized an allele of klp‐4 that contains are large indel in the cargo binding domain of the motor, however, the gene still appears to be expressed. Behavioral analysis demonstrated that klp‐4 mutants have defects in locomotive signaling, but not the strikingly uncoordinated movements such as those found in unc‐104/KIF1A mutants. Animals with this large deletion are hypersensitive to the acetylcholinesterase inhibitor aldicarb but are unaffected by exogenous serotonin. Interestingly, this large klp‐4 indel does not affect gross neuronal development but does lead to aggregation and disorganization of RAB‐3 at synapses. Taken together, these data suggest a role for KLP‐4 in modulation of cholinergic signaling in vivo and shed light on possible in vivo mechanisms of Kinesin‐3 motor regulation.
Highlights
The dynein and kinesin protein families are ATP dependent molecular motors that move along polarized microtubules in virtually all cell types
Slight differences exist in kinesin motor domains, there exists a high degree of conservation, both structurally and mechanistically, both within and between species
Klp‐4 mutants had ectopic blebbing and general disorganization of RAB‐3 positive synaptic vesicles (SVs) in ventral nerve cord (VNC) interneurons (Figure 4E and F). These phenotypes were highly penetrant in klp‐4(ok3537) mutants. These results suggest that the klp‐4(ok3537) mutation results in altered locomotive behavior based on the inability to correctly organize the VNC
Summary
The dynein and kinesin protein families are ATP dependent molecular motors that move along polarized microtubules in virtually all cell types Both groups of motors traffic various cargoes within cells, including organelles, and vesicles. The function of KLP‐6 has been closely tied to head ciliated sensory neurons, where KLP‐6 is integral to the release of ciliary vesicles into the environment.[19] KLP‐4 is the least well understood Kinesin‐3 in C elegans Previous work on this motor in the context of trafficking the glutamate receptor, GLR‐1, in neurons, where klp‐4 loss of function alleles conferred glutamatergic signaling defects.[17,20]. Locomotive phenotypes can be rescued by overexpression of the wild type motor These data establish a general role of KLP‐4 and gives mechanistic insight into how Kinesin‐3 motors function in vivo
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