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

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. We generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockout...

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Published in:	Biological psychiatry (1969) Vol. 90; no. 5; pp. 295 - 306
Main Authors:	Levy, Jenna A., LaFlamme, Christy W., Tsaprailis, George, Crynen, Gogce, Page, Damon T.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-09-2021
Subjects:	Animals Autism Spectrum Disorder Cerebral cortex Dyrk Kinases Dyrk1a Mice Microcephaly mTOR Mutation - genetics Neuronal growth Protein Serine-Threonine Kinases - genetics Protein-Tyrosine Kinases - genetics Pyramidal Cells - pathology mTOR Cerebral cortex Neuronal growth Microcephaly Dyrk1a Autism spectrum disorder
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Summary:	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. 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. We found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phosphoproteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB-BDNF (tyrosine receptor kinase B–brain-derived neurotrophic factor), an important regulator of ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) and mTOR (mammalian target of rapamycin) signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1 (insulin-like growth factor-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. In addition, these data position Dyrk1a within a larger group of autism spectrum disorder/intellectual disability risk genes that impinge on growth-associated signaling cascades to regulate brain size and connectivity, suggesting a point of convergence for multiple autism etiologies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: J.L. and D.T.P. conceived of and designed experiments. J.L. executed experiments and data analysis except for in vitro primary neuronal culture experiments, which were performed and analyzed by C.W.L., and TMT/Mass Spectrometry experiments, which were conducted by G.T and analyzed by G.C. Data interpretation by J.L., C.W.L, G.T., G.C., and D.T.P. J.L. and D.T.P. wrote the paper and J.L., C.W.L., G.T., G.C., and D.T.P. edited the paper.
ISSN:	0006-3223 1873-2402
DOI:	10.1016/j.biopsych.2021.01.012