The conserved mitogen activated kinase kinase kinase (MAPKKK) DLKs play critical roles in neuronal process growth, synapse formation and axon regeneration. DLKs also act as sensors to mediate neuronal responses to different stresses, including microtubule (MT) disruption. However, it is not clear in which contexts DLKs sense MT stress and which signaling transduction mechanisms control the activity of DLKs to mediate specific functional outcomes. In C. elegans the DLK ortholog DLK-1 is normally expressed in most neurons at low levels. From a forward genetic screen for mutants displaying aberrant DLK-1 levels or localization, we identified a mutant that exhibited aggregated DLK-1 in neuronal soma. Using whole genome sequencing and genetic mapping, we determined that this mutation affected
ben-1, one of six beta-tubulin isotypes in C. elegans. Levels of the transcription factor CEBP-1, a downstream target induced by DLK-1, were elevated in neurons of
ben-1 mutants. These findings suggest that altering
ben-1 function activates
dlk-1, resulting in
cebp-1 dependent transcription. A
ben-1 transcriptional reporter is exclusively expressed in neurons. BEN-1 is known to convey the sensitivity to benomyl1, a microtubule-targeting compound used for killing parasitic nematodes and treating cancers. We found that benomyl treatment also caused neural DLK-1 aggregation, CEBP-1 elevation, as well as neuronal defects such as impaired synaptogenesis. Altogether, our findings suggest that changes in neuronal beta-tubulin BEN-1 containing MT cytoskeleton elicit specific stress responses to activate
dlk-1/cebp-1 signaling. 1. Driscoll, M., Dean, E., Reilly, E., Bergholz, E., and Chalfie, M. (1989). Genetic and molecular analysis of a Caenorhabditis elegans beta-tubulin that conveys benzimidazole sensitivity. J. Cell Biol. 109, 2993-3003.