The role of Goldilocks protein kinase DYRK1A in embryonic development.

DYRK1A (Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) is a dosage-sensitive gene whose expression must be tightly regulated to support normal development. This is supported by studies in animal models which demonstrate that both insufficient and excessive DYRK1A/Dyrk1a activity can impair development across multiple organ systems. In humans, both gain and loss-of-function alterations can disrupt the levels of DYRK1A, leading to structural birth defects and neurodevelopmental disorders. For example, DYRK1A haploinsufficiency causes DYRK1A syndrome, marked by intellectual disability and characteristic craniofacial features. DYRK1A is located on chromosome 21, and its overexpression in the context of trisomy 21 is believed to contribute to the developmental anomalies and comorbidities seen in Down syndrome. Notably, normalizing DYRK1A genetically or pharmacologically in Down syndrome mouse models can partially rescue phenotypes, underscoring its pathogenic role in this genetic condition. This review highlights the critical need to understand the effects of altering DYRK1A dosage during embryogenesis to inform therapeutic strategies for DYRK1A related disorders and Down syndrome associated birth defects.