Dyrk1a Mutations Cause Undergrowth of Cortical Pyramidal Neurons via Dysregulated Growth Factor Signaling.

Background: Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood.

Methods: We generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockouts, to investigate the necessity of Dyrk1a in the cortex during development. We used unbiased, high-throughput phosphoproteomics to identify dysregulated signaling mechanisms in the developing Dyrk1a mutant cortex as well as classic genetic modifier approaches and pharmacological therapeutic intervention to rescue microcephaly and neuronal undergrowth caused by Dyrk1a mutations.