Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment
- University of Texas Southwestern Medical Center, United States
- Máxima Medical Center, Netherlands
- St George's University Hospitals, NHS Foundation Trust, United Kingdom
- Queen Mary University of London, United Kingdom
- University of Pennsylvania, United States
- Leiden University Medical Center, Netherlands
Abstract
Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (1), autism spectrum disorder (2), intellectual disability (3), and corpus callosum agenesis (4). In addition, ARID1B is the most common cause of Coffin-Siris Syndrome, a developmental delay syndrome characterized by some of the above abnormalities (5-7). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth Hormone Releasing Hormone (GHRH) and Growth Hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.
Data availability
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RNA-seq transcriptonal profiling in whole hippocampus in WT and Arid1b+/- micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE92238).
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mouse_e11.5_forebrain_smarca4-flagvailable at the NCBI Gene Expression Omnibus (accession no: GSM912547).
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Genome-Wide Transcriptional Regulation Mediated By Biochemically Distinct Forms of SWI/SNFPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE69568).
Article and author information
Author details
Funding
Hamon Center for Regenerative Science and Medicine
- Cemre Celen
- Xuxu Sun
National Institutes of Health (DA023555)
- Amelia J Eisch
National Institutes of Health (MH107945)
- Amelia J Eisch
Postdoctoral Institutional training grant (NIDA T32-DA007290)
- Angela K Walker
HHMI International Fellowship
- Liem H Nguyen
Pollack Foundation
- Hao Zhu
National Institutes of Health (1K08CA157727)
- Hao Zhu
National Cancer Institute (1R01CA190525)
- Hao Zhu
Burroughs Wellcome Fund
- Hao Zhu
CPRIT New Investigator Award (R1209)
- Hao Zhu
CPRIT Early Translation Grant (DP150077)
- Hao Zhu
National Institutes of Health (DA023701)
- Amelia J Eisch
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Revised ethics statement: All animal procedures were based on animal care guidelines approved by the Institutional. Animal Care and Use Committee at University of Texas Southwestern Medical Center (UTSW). Animal protocol number is 2015-101118. Patient data included in the article is non-identifiable data, and hence does not require approval from the patient/parents.
Human subjects: All animal procedures were based on animal care guidelines approved by the Institutional. Animal Care and Use Committee at University of Texas Southwestern Medical Center (UTSW). Animal protocol number is 2015-101118. Patient data included in the article is non-identifiable data, and hence does not require approval from the patients.
Copyright
© 2017, Zhu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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