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

  1. Cemre Celen
  2. Jen-Chieh Chuang
  3. Xin Luo
  4. Nadine Nijem
  5. Angela K Walker
  6. Fei Chen
  7. Shuyuan Zhang
  8. Andrew Seungjae Chung
  9. Liem H Nguyen
  10. Ibrahim Nassour
  11. Albert Budhipramono
  12. Xuxu Sun
  13. Levinus A Bok
  14. Meriel McEntagart
  15. Evelien Gevers
  16. Shari G Birnbaum
  17. Amelia J Eisch
  18. Craig M Powell
  19. Woo-Ping Ge
  20. Gijs WE Santen
  21. Maria Chahrour
  22. Hao Zhu  Is a corresponding author
  1. UT Southwestern Medical Center, United States
  2. University of Texas Southwestern Medical Center, United States
  3. Máxima Medical Center, Netherlands
  4. St George's University Hospitals, NHS Foundation Trust, United Kingdom
  5. Queen Mary University of London, United Kingdom
  6. University of Pennsylvania, United States
  7. 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

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Cemre Celen

    The Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. 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.
  3. 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.
  4. Nadine Nijem

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Levinus A Bok

    Department of Pediatrics, Máxima Medical Center, Veldhoven, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. Gijs WE Santen

    Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  21. Maria Chahrour

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8417-9698

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.

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Version history

  1. Received: February 3, 2017
  2. Accepted: June 24, 2017
  3. Accepted Manuscript published: July 11, 2017 (version 1)
  4. Accepted Manuscript updated: July 13, 2017 (version 2)
  5. Version of Record published: July 18, 2017 (version 3)

Copyright

© 2017, Celen 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

  • 4,745
    Page views
  • 768
    Downloads
  • 74
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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)

  1. Cemre Celen
  2. Jen-Chieh Chuang
  3. Xin Luo
  4. Nadine Nijem
  5. Angela K Walker
  6. Fei Chen
  7. Shuyuan Zhang
  8. Andrew Seungjae Chung
  9. Liem H Nguyen
  10. Ibrahim Nassour
  11. Albert Budhipramono
  12. Xuxu Sun
  13. Levinus A Bok
  14. Meriel McEntagart
  15. Evelien Gevers
  16. Shari G Birnbaum
  17. Amelia J Eisch
  18. Craig M Powell
  19. Woo-Ping Ge
  20. Gijs WE Santen
  21. Maria Chahrour
  22. Hao Zhu
(2017)
Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment
eLife 6:e25730.
https://doi.org/10.7554/eLife.25730

Share this article

https://doi.org/10.7554/eLife.25730

Further reading

    1. Developmental Biology
    2. Neuroscience
    Wen Wang, Xiao Zhang ... Zi-Bing Jin
    Research Article Updated

    Chimeric RNAs have been found in both cancerous and healthy human cells. They have regulatory effects on human stem/progenitor cell differentiation, stemness maintenance, and central nervous system development. However, whether they are present in human retinal cells and their physiological functions in the retinal development remain unknown. Based on the human embryonic stem cell-derived retinal organoids (ROs) spanning from days 0 to 120, we present the expression atlas of chimeric RNAs throughout the developing ROs. We confirmed the existence of some common chimeric RNAs and also discovered many novel chimeric RNAs during retinal development. We focused on CTNNBIP1-CLSTN1 (CTCL) whose downregulation caused precocious neuronal differentiation and a marked reduction of neural progenitors in human cerebral organoids. CTCL is universally present in human retinas, ROs, and retinal cell lines, and its loss-of-function biases the progenitor cells toward retinal pigment epithelial cell fate at the expense of retinal cells. Together, this work provides a landscape of chimeric RNAs and reveals evidence for their critical role in human retinal development.

    1. Neuroscience
    Peibo Xu, Jian Peng ... Yuejun Chen
    Research Article

    Deciphering patterns of connectivity between neurons in the brain is a critical step toward understanding brain function. Imaging-based neuroanatomical tracing identifies area-to-area or sparse neuron-to-neuron connectivity patterns, but with limited throughput. Barcode-based connectomics maps large numbers of single-neuron projections, but remains a challenge for jointly analyzing single-cell transcriptomics. Here, we established a rAAV2-retro barcode-based multiplexed tracing method that simultaneously characterizes the projectome and transcriptome at the single neuron level. We uncovered dedicated and collateral projection patterns of ventromedial prefrontal cortex (vmPFC) neurons to five downstream targets and found that projection-defined vmPFC neurons are molecularly heterogeneous. We identified transcriptional signatures of projection-specific vmPFC neurons, and verified Pou3f1 as a marker gene enriched in neurons projecting to the lateral hypothalamus, denoting a distinct subset with collateral projections to both dorsomedial striatum and lateral hypothalamus. In summary, we have developed a new multiplexed technique whose paired connectome and gene expression data can help reveal organizational principles that form neural circuits and process information.