DYRK1A ortholog mbk-1 knockout in Caenorhabditis elegans as a tool for genetics research of developmental disorders

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 uncover developmental roles that may inform function of mammalian Dyrk1a. 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 roles of mbk-1 in development. Preference index assays to assess 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, suggesting a 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 that EK228 may be a useful model for studying the developmental effects of mbk-1 and implicate the gene in fundamental functions in adaptive movement in the simplified nervous system of C. elegans. Further understanding of this model could provide insight into the early roles of Dyrk1a in mammalian development. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/686526v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@ceeda9org.highwire.dtl.DTLVardef@15526faorg.highwire.dtl.DTLVardef@171f51aorg.highwire.dtl.DTLVardef@92b92c_HPS_FORMAT_FIGEXP M_FIG C_FIG (Created with BioRender) Article summaryThis work provides insight into evolutionarily conserved functions of the protein kinase DYRK1A, which is linked to developmental disorders including Down syndrome and DYRK1A syndrome. Caenorhabditis elegans with a genetic ablation of the DYRK1A ortholog, mbk-1, were used to examine potential roles in movement, chemosensing, and associative learning and memory. The findings indicate a role of mbk-1 in C. elegans movement and foraging behavior, which may provide insight into some of the cellular and neural mechanisms being influenced by DYRK1A. Understanding of the protein kinase DYRK1A may help to elucidate novel therapeutic pathways for developmental disorders.