Loss of DYRK1A ortholog mbk-1 impairs locomotor behavior in Caenorhabditis elegans.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dosage sensitive gene located on human chromosome 21 (Hsa21) that contributes to phenotypes associated with developmental disorders like Down syndrome and DYRK1A haploinsufficiency syndrome. Complete genetic knockout of Dyrk1a from conception is embryonic lethal, presenting a barrier in its study. The mbk-1 gene in Caenorhabditis elegans has been identified as an ortholog to mammalian Dyrk1a, and genetic knockout of mbk-1 in C. elegans is not lethal. We hypothesized that deletion of the mbk-1 gene would alter chemosensory function, learning, and motility in C. elegans, and that these phenotypes would be recovered using a humanized DYRK1A replacement at the endogenous mbk-1 locus. Using behavioral preference index assays, analyses of locomotion, and learning in classical conditioning procedures, an mbk-1 knockout strain of C. elegans, EK228, was characterized to identify potential behavioral roles of mbk-1. Preference index assays assessing chemosensory capabilities determined that mbk-1 deletion yielded no detrimental effects. Thrashing and foraging behavior analyses uncovered significant deficits in movement in the EK228 C. elegans, which were not present in two mbk-1 replacement strains containing humanized DYRK1A, suggesting an essential role of mbk-1 in locomotion and motility. Lastly, classical conditioning revealed no significant deficits in the abilities of the EK228 strain in forming associative connections between stimuli. Overall, these results imply functional conservation of the mbk-1/DYRK family kinases, and provide support for the use of humanized replacement strains of C. elegans for the study of mammalian genes.