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
-
RNA-seq transcriptonal profiling in whole hippocampus in WT and Arid1b+/- micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE92238).
-
mouse_e11.5_forebrain_smarca4-flagvailable at the NCBI Gene Expression Omnibus (accession no: GSM912547).
-
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.
Reviewing Editor
- Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States
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.
Version history
- Received: February 3, 2017
- Accepted: June 24, 2017
- Accepted Manuscript published: July 11, 2017 (version 1)
- Accepted Manuscript updated: July 13, 2017 (version 2)
- Version of Record published: July 18, 2017 (version 3)
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.
Metrics
-
- 4,910
- views
-
- 776
- downloads
-
- 80
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment
eLife 6:e25730.
https://doi.org/10.7554/eLife.25730
Further reading
-
- Neuroscience
The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor long form (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determined the role of glutamatergic neurotransmission from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces luteinizing hormone (LH) release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LeprCre (LepRb-Cre) mice. We collected blood sequentially before and for 1 hr after intravenous clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of Fos immunoreactive neurons in the PMv. Next, females with deletion of Slc17a6 (Vglut2) in LepRb neurons (LeprΔVGlut2) showed delayed age of puberty, disrupted estrous cycles, increased gonadotropin-releasing hormone (GnRH) concentration in the axon terminals, and disrupted LH secretion, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LeprloxTB) with concomitant deletion of Slc17a6 (Vglut2flox) mice. Rescue of Lepr and deletion of Slc17a6 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LeprloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation, and became pregnant, while LeprloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic neurotransmission from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.
-
- Neuroscience
The basolateral amygdala (BLA), a brain center of emotional expression, contributes to acoustic communication by first interpreting the meaning of social sounds in the context of the listener’s internal state, then organizing the appropriate behavioral responses. We propose that modulatory neurochemicals such as acetylcholine (ACh) and dopamine (DA) provide internal-state signals to the BLA while an animal listens to social vocalizations. We tested this in a vocal playback experiment utilizing highly affective vocal sequences associated with either mating or restraint, then sampled and analyzed fluids within the BLA for a broad range of neurochemicals and observed behavioral responses of adult male and female mice. In male mice, playback of restraint vocalizations increased ACh release and usually decreased DA release, while playback of mating sequences evoked the opposite neurochemical release patterns. In non-estrus female mice, patterns of ACh and DA release with mating playback were similar to males. Estrus females, however, showed increased ACh, associated with vigilance, as well as increased DA, associated with reward-seeking. Experimental groups that showed increased ACh release also showed the largest increases in an aversive behavior. These neurochemical release patterns and several behavioral responses depended on a single prior experience with the mating and restraint behaviors. Our results support a model in which ACh and DA provide contextual information to sound analyzing BLA neurons that modulate their output to downstream brain regions controlling behavioral responses to social vocalizations.
