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

  1. Hao Zhu  Is a corresponding author
  2. Cemre Celen
  3. Jen-Chieh Chuang
  4. Xin Luo
  5. Nadine Nijem
  6. Angela K Walker
  7. Fei Chen
  8. Shuyuan Zhang
  9. Andrew Seungjae Chung
  10. Liem H Nguyen
  11. Ibrahim Nassour
  12. Albert Budhipramono
  13. Xuxu Sun
  14. Levinus A Bok
  15. Meriel McEntagart
  16. Evelien Gevers
  17. Shari G Birnbaum
  18. Amelia J Eisch
  19. Craig M Powell
  20. Woo-Ping Ge
  21. Gijs WE Santen
  22. Maria Chahrour
  1. University of Texas Southwestern Medical Center, United States
  2. Máxima Medical Center, Netherlands
  3. St George's University Hospitals, NHS Foundation Trust, United Kingdom
  4. Queen Mary University of London, United Kingdom
  5. University of Pennsylvania, United States
  6. Leiden University Medical Center, Netherlands
Research Article
  • Cited 47
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Cite this article as: eLife 2017;6:e25730 doi: 10.7554/eLife.25730

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. 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
  2. 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.
  3. 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.
  4. 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.
  5. Nadine Nijem

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

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

    Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  22. 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.

Reviewing Editor

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

Publication 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, 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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Further reading

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    P Christiaan Klink et al.
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    Population receptive field (pRF) modeling is a popular fMRI method to map the retinotopic organization of the human brain. While fMRI-based pRF maps are qualitatively similar to invasively recorded single-cell receptive fields in animals, it remains unclear what neuronal signal they represent. We addressed this question in awake nonhuman primates comparing whole-brain fMRI and large-scale neurophysiological recordings in areas V1 and V4 of the visual cortex. We examined the fits of several pRF models based on the fMRI blood-oxygen-level-dependent (BOLD) signal, multi-unit spiking activity (MUA), and local field potential (LFP) power in different frequency bands. We found that pRFs derived from BOLD-fMRI were most similar to MUA-pRFs in V1 and V4, while pRFs based on LFP gamma power also gave a good approximation. fMRI-based pRFs thus reliably reflect neuronal receptive field properties in the primate brain. In addition to our results in V1 and V4, the whole-brain fMRI measurements revealed retinotopic tuning in many other cortical and subcortical areas with a consistent increase in pRF size with increasing eccentricity, as well as a retinotopically specific deactivation of default mode network nodes similar to previous observations in humans.

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    The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.