Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment

Abstract
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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

The following data sets were generated

1. Celen C
2. Chuang J
3. Luo X
4. Zhu H
(2016) RNA-seq transcriptonal profiling in whole hippocampus in WT and Arid1b+/- mice
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE92238).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE92238

The following previously published data sets were used

(2014) mouse_e11.5_forebrain_smarca4-flag
vailable at the NCBI Gene Expression Omnibus (accession no: GSM912547).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM912547
(2015) Genome-Wide Transcriptional Regulation Mediated By Biochemically Distinct Forms of SWI/SNF
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE69568).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69568

Article and author information

Author details

Hao Zhu

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
Hao.Zhu@utsouthwestern.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8417-9698
Cemre Celen

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Jen-Chieh Chuang

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Xin Luo

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Nadine Nijem

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Angela K Walker

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Fei Chen

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Shuyuan Zhang

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Andrew Seungjae Chung

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Liem H Nguyen

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Ibrahim Nassour

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Albert Budhipramono

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Xuxu Sun

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Levinus A Bok

Department of Pediatrics, Máxima Medical Center, Veldhoven, Netherlands

Competing interests
The authors declare that no competing interests exist.
Meriel McEntagart

Medical Genetics, St George's University Hospitals, NHS Foundation Trust, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Evelien Gevers

William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Shari G Birnbaum

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Amelia J Eisch

Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Craig M Powell

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Woo-Ping Ge

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Gijs WE Santen

Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands

Competing interests
The authors declare that no competing interests exist.
Maria Chahrour

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.

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

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.