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

Cemre Celen, Jen Chieh Chuang, Xin Luo, Nadine Nijem, Angela K. Walker, Fei Chen, Shuyuan Zhang, Andrew S. Chung, Liem H. Nguyen, Ibrahim Nassour, Albert Budhipramono, Xuxu Sun, Levinus A. Bok, Meriel McEntagart, Evelien F. Gevers, Shari G. Birnbaum, Amelia J. Eisch, Craig M. Powell, Woo Ping Ge, Gijs W.E. SantenMaria Chahrour, Hao Zhu

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere25730
JournaleLife
Volume6
DOIs
StatePublished - Jul 11 2017

Fingerprint

Haploinsufficiency
Chromatin Assembly and Disassembly
Growth Hormone
Chromatin
Agenesis of Corpus Callosum
Phenotype
Dissection
Growth Hormone-Releasing Hormone
Social Behavior
Muscle Weakness
Somatomedins
Growth
Intellectual Disability
Muscle
Brain
Anxiety
Genes
Coffin-Siris syndrome
Insulin-Like Growth Factor I Deficiency
Autism Spectrum Disorder

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. / Celen, Cemre; Chuang, Jen Chieh; Luo, Xin; Nijem, Nadine; Walker, Angela K.; Chen, Fei; Zhang, Shuyuan; Chung, Andrew S.; Nguyen, Liem H.; Nassour, Ibrahim; Budhipramono, Albert; Sun, Xuxu; Bok, Levinus A.; McEntagart, Meriel; Gevers, Evelien F.; Birnbaum, Shari G.; Eisch, Amelia J.; Powell, Craig M.; Ge, Woo Ping; Santen, Gijs W.E.; Chahrour, Maria; Zhu, Hao.

In: eLife, Vol. 6, e25730, 11.07.2017.

Research output: Contribution to journalArticle

Celen, C, Chuang, JC, Luo, X, Nijem, N, Walker, AK, Chen, F, Zhang, S, Chung, AS, Nguyen, LH, Nassour, I, Budhipramono, A, Sun, X, Bok, LA, McEntagart, M, Gevers, EF, Birnbaum, SG, Eisch, AJ, Powell, CM, Ge, WP, Santen, GWE, Chahrour, M & Zhu, H 2017, 'Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment', eLife, vol. 6, e25730. https://doi.org/10.7554/eLife.25730
Celen, Cemre ; Chuang, Jen Chieh ; Luo, Xin ; Nijem, Nadine ; Walker, Angela K. ; Chen, Fei ; Zhang, Shuyuan ; Chung, Andrew S. ; Nguyen, Liem H. ; Nassour, Ibrahim ; Budhipramono, Albert ; Sun, Xuxu ; Bok, Levinus A. ; McEntagart, Meriel ; Gevers, Evelien F. ; Birnbaum, Shari G. ; Eisch, Amelia J. ; Powell, Craig M. ; Ge, Woo Ping ; Santen, Gijs W.E. ; Chahrour, Maria ; Zhu, Hao. / Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. In: eLife. 2017 ; Vol. 6.
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abstract = "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.",
author = "Cemre Celen and Chuang, {Jen Chieh} and Xin Luo and Nadine Nijem and Walker, {Angela K.} and Fei Chen and Shuyuan Zhang and Chung, {Andrew S.} and Nguyen, {Liem H.} and Ibrahim Nassour and Albert Budhipramono and Xuxu Sun and Bok, {Levinus A.} and Meriel McEntagart and Gevers, {Evelien F.} and Birnbaum, {Shari G.} and Eisch, {Amelia J.} and Powell, {Craig M.} and Ge, {Woo Ping} and Santen, {Gijs W.E.} and Maria Chahrour and Hao Zhu",
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AU - Celen, Cemre

AU - Chuang, Jen Chieh

AU - Luo, Xin

AU - Nijem, Nadine

AU - Walker, Angela K.

AU - Chen, Fei

AU - Zhang, Shuyuan

AU - Chung, Andrew S.

AU - Nguyen, Liem H.

AU - Nassour, Ibrahim

AU - Budhipramono, Albert

AU - Sun, Xuxu

AU - Bok, Levinus A.

AU - McEntagart, Meriel

AU - Gevers, Evelien F.

AU - Birnbaum, Shari G.

AU - Eisch, Amelia J.

AU - Powell, Craig M.

AU - Ge, Woo Ping

AU - Santen, Gijs W.E.

AU - Chahrour, Maria

AU - Zhu, Hao

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