Elsevier

Biological Psychiatry

Volume 90, Issue 5, 1 September 2021, Pages 295-306
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2021.01.012Get rights and content

Abstract

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.

Results

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.

Conclusions

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.

Section snippets

Methods and Materials

See the Supplement for more details.

Conditional Mutations in Dyrk1a Cause Microcephaly and ASD-Relevant Behaviors

To circumvent pleiotropic effects outside the brain and isolate the effects of the Dyrk1a mutation in the cerebral cortex, which is heavily affected in microcephaly, we used a conditional approach. Using an Emx1-cre driver, which is expressed in approximately 88% of neurons in the neocortex and hippocampus as well as a subset of cells in the astrocyte and oligodendrocyte lineages (34), we generated heterozygous (Emx1-cre+; Dyrk1aloxP/+, conditional heterozygous [cHet]) and homozygous (Emx1-cre+

Discussion

DYRK1A haploinsufficiency causes ASD, ID, and microcephaly in humans (4,5). Trisomy of chromosome 21 (including DYRK1A) causes Down syndrome and microcephaly (OMIM #190685). These patient genetic findings confirm a critical role of Dyrk1a in regulating brain growth and the development of behavior and cognition. Utilizing both heterozygous and homozygous conditional mutants enabled us to study a clinically relevant model with similar construct validity to patients and a loss-of-function model to

Acknowledgments and Disclosures

This work is supported by National Institutes of Health Grant No. RO1MH108519 (to DTP), gift funds from Ms. Nancy Lurie Marks (to DTP), and fellowship support from the RJ Foundation (to JAL).

JAL and DTP conceived of and designed experiments. JAL executed experiments and data analysis with the exception of in vitro primary neuronal culture experiments, which were performed and analyzed by CWL, and tandem mass tag/mass spectrometry experiments, which were conducted by GT and analyzed by GC. Data

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