Archival ReportDyrk1a Mutations Cause Undergrowth of Cortical Pyramidal Neurons via Dysregulated Growth Factor Signaling
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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