4.8 Article

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

Journal

ELIFE
Volume 6, Issue -, Pages -

Publisher

ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.25730

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Funding

  1. Hamon Center for Regenerative Science and Medicine
  2. NIDA [T32-DA007290]
  3. HHMI International Student Research Fellowship
  4. National Institutes of Health [DA023701, DA023555, MH107945, K99/R00 (R00NS073735), R21(NS099950), 1K08CA157727]
  5. Pollock Foundation
  6. National Cancer Institute [1R01CA190525]
  7. Burroughs Wellcome Fund
  8. CPRIT New Investigator Award [R1209]
  9. CPRIT Early Translation Grant [DP150077]
  10. University of Texas Southwestern Medical Center
  11. NARSAD [NARSAD 24951]
  12. Cancer Prevention and Research Institute of Texas [RP150596]
  13. Barts Health NHS Trust
  14. Queen Mary University London

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Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). 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.

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