Abstract
Genetic evidence indicates that haploinsufficiency of ARID1B causes intellectual disability (ID) and autism spectrum disorder (ASD), but the neural function of ARID1B is largely unknown. Using both conditional and global Arid1b knockout mouse strains, we examined the role of ARID1B in neural progenitors. We detected an overall decrease in the proliferation of cortical and ventral neural progenitors following homozygous deletion of Arid1b, as well as altered cell cycle regulation and increased cell death. Each of these phenotypes was more pronounced in ventral neural progenitors. Furthermore, we observed decreased nuclear localization of β-catenin in Arid1b-deficient neurons. Conditional homozygous deletion of Arid1b in ventral neural progenitors led to pronounced ID- and ASD-like behaviors in mice, whereas the deletion in cortical neural progenitors resulted in minor cognitive deficits. This study suggests an essential role for ARID1B in forebrain neurogenesis and clarifies its more pronounced role in inhibitory neural progenitors. Our findings also provide insights into the pathogenesis of ID and ASD.
Highlights
Haploinsufficient mice, suggesting that E/I imbalance may play a role in the pathology of ARID1B-related neurodevelopment disorders
We peritoneally injected all pregnant dams with bromodeoxyuridine (BrdU), a thymidine analog that is incorporated into dividing cells during DNA replication[32,33,34], and found no significant decrease in the percentage of BrdU-positive cortical neural progenitors in Emx-Arid1b mice harvested 1 h postinjection (20.04%), compared with controls (29.67%) (Fig. 1B,C)
As we and other groups have recently reported, deletion of one Arid1b allele in mice is sufficient to cause significant behavioral deficiencies, recapitulating intellectual disability (ID) and autism spectrum disorder (ASD) behavioral p henotypes[26,27,28]. These mouse models of Arid1b haploinsufficiency are useful because they mirror the gene dosage effects seen in human patients, but are less useful for deciphering the neurobiological function of the ARID1B protein, whose levels remain above fifty percent in Arid1b mutant heterozygotes, compared to their wild-type littermates[26,27,28]
Summary
Haploinsufficient mice, suggesting that E/I imbalance may play a role in the pathology of ARID1B-related neurodevelopment disorders. We report impaired proliferation in the cortical neural progenitor population and, to a greater extent, in ventral neural progenitors. This may be due to altered cell cycle regulation, as we observe decreased cell cycle speed in ventral neural progenitors with homozygous Arid1b deletion and a decreased rate of cell cycle re-entry in both cortical and ventral neural progenitors. In both progenitor populations we report an increased number of apoptotic cells. Arid1b conditional homozygous deletion has an outsize effect on ventral progenitor proliferation, which is intricately linked to animal behavior, whereas homozygous loss of Arid1b in cortical progenitors gives rise to comparatively moderate neural and behavioral phenotypes
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