Author(s): Jenna Levy, Scripps Research; Jenna Levy, Scripps Research; Christy LaFlamme, Florida Atlantic University; George Tsaprailis, Scripps Research; Gogce Crynen, Scripps Research; Damon T. Page, Scripps Research //

ABSTRACT: Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder (ASD), and intellectual disability (ID); however, the underlying cellular and molecular mechanisms are not well understood. 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 employed unbiased, high throughput phospho-proteomics 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. We found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phospho-proteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB/BDNF, an important regulator of ERK/MAPK and mTOR signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1, both of which impinge on these signaling cascades, rescued microcephaly and neuronal undergrowth in neonatal mutants. Altogether, these findings identify a previously unknown mechanism through which Dyrk1a mutations disrupt growth factor signaling in the developing brain, thus influencing neuronal growth and connectivity. Our results place Dyrk1a as a critical regulator of a biological pathway known to be dysregulated in humans with autism spectrum disorder and intellectual disability. Additionally, these data position Dyrk1a within a larger group of ASD/ID risk genes that impinge on growth-associated signaling cascades to regulate brain growth and connectivity, suggesting a point of convergence for multiple autism etiologies.

Source of Funding: National Institute of Health (NIH) grant RO1MH108519