Dyrk1a is required for craniofacial development inXenopus laevis

Abstract

Loss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis. Dyrk1a mRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with DYRK1A mutations.

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“…S3A ). This indicates that Dyrk1a is required earlier in the embryo for neural crest development, a finding that is corroborated by a recent preprint 32 .…”

“…ENCCs develop exclusively from the neural crest 29,36 , and our group and others have observed dyrk1a expression in the Xenopus neural crest 25,31,32 . Therefore, this migration phenotype could be due to earlier neural crest developmental defects.…”

“…Next we elaborated this finding for dyrk1a in Xenopus, given our previous experience perturbing this gene within the central nervous system and the abundance of associated molecular tools 6,25,31,32 . We observed that dyrk1a is expressed in ENCCs during migration (Fig.…”