MAPK‐15 is a ciliary protein required for PKD‐2 localization and male mating behavior in Caenorhabditis elegans

Abstract

Cilia are conserved cellular structures that facilitate sensory-based processes, including those required for neuronal and kidney functions. Here, we show that the human mitogen activated kinase-15 (MAPK-15) ortholog in Caenorhabditis elegans encodes a ciliary protein. A strain harboring a mutation in the catalytic site of the kinase domain results in ciliary-specific defects in tail neurons of both hermaphrodite and male worms, manifesting in dye uptake, dendrite extension, and male mating behavior defects. Transgenic-fusion constructs for two mapk-15 isoforms (A and C) with full-length kinase domains were generated. Expression of either the A- or C-specific isoform rescues the dye-filling and male-mating defective phenotypes, confirming the ciliary function of mapk-15. Expression of mapk-15 occurs in many ciliated-sensory neurons of the head and tail in hermaphrodite and male worms. Localization of MAPK-15 isoforms A and C occurs in the cell body, dendritic processes, and cilia. A C. elegans ortholog of polycystin-2, a protein that when defective in mammals results in autosomal dominant polycystic kidney disease, is mislocalized in the male ray neurons of mapk-15 mutant worms. Expression of the mapk-15 gene by the pkd-2 promoter partially rescues the male-mating defects observed in mapk-15 mutant animals. Expression of mapk-15 is DAF-19/RFX dependent in some CSNs and DAF-19/RFX independent in others. Collectively, these data suggest that MAPK-15 functions upstream of PKD-2 localization to modulate ciliary sensory functions.

Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 inCaenorhabditis elegansand Human Cells

“…MAPK15 is also required for correct localization of ciliary axonemal proteins including ciliogenic trafficking regulators (BBS7 and ARL-13), and subsets of sensory signaling molecules. In ad-dition, MAPK-15 has very recently been shown to regulate the ciliary localization of the PKD-2 polycystin transmembrane protein in males (Piasecki et al 2017). Thus, MAPK15 regulates the distribution of a wide range of ciliary transportassociated proteins linked to cilium formation and function.…”

A neuronal MAP kinase constrains growth of aC. eleganssensory dendrite throughout the life of the organism

“…Together, these data indicate that disruption of C05D10.2 causes URX overgrowth. [39][40][41]. As URX is neither ciliated nor dopaminergic, it is unclear how these roles relate to URX overgrowth.…”

“…To determine where mapk-15 is expressed, we generated a transcriptional reporter and found that it labels URX as well as many other head sensory neurons at all larval stages ( Fig. 4A; expression in ciliated sensory neurons is also reported in [39][40][41]), suggesting mapk-15 could act cell-autonomously in URX.…”

“…Second, its interaction with autophagic components is mediated through its conserved LC3interacting region [49], which we found to be required to restrict dendrite growth. Third, in C. elegans ciliated neurons, MAPK-15 localizes near the periciliary membrane compartment, a region that is enriched for proteins involved in membrane trafficking [40,41]. Fourth, the role of MAPK-15 in C. elegans dopaminergic neurons has been suggested to involve membrane trafficking of a dopamine transporter at synapses [39].…”

“…Piasecki et al, Kazastaya et al, and Bermingham et al report localization of MAPK-15 in sensory cilia and at dopaminergic synapses of certain ciliated sensory neurons [39-41]. Loss of MAPK-15 leads to altered sensory cilia morphology, defects in mating behaviors mediated by ciliated sensory neurons and defects in swimming behaviors affected by dopamine signaling[39][40][41]. While URX is not ciliated, these results are consistent with the idea that MAPK-15 acts at subcellular sensory compartments.…”