Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment
Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment
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DOI：
10.7554/elife.25730
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发表时间：
2017-07-11
期刊：
影响因子：
7.7
通讯作者：
Zhu, Hao
中科院分区：
文献类型：
--
作者：
Celen, Cemre;Chuang, Jen-Chieh;Zhu, Hao
测序研究表明，ARID 1B（SWI/SNF染色质重塑亚基）的单倍不足与身材矮小有关（Yu et al.，2015）、自闭症谱系障碍（O 'Roak等人，2012）、智力残疾（Deciphering Developmental Disorders Study，2015）和胼胝体发育不全（Halgren et al.，2012年）。此外，ARID 1B是Coffin-Siris综合征的最常见原因，Coffin-Siris综合征是一种以上述异常中的一些为特征的发育迟缓综合征（Santen等人，2012; Tsurusaki等人，2012; Wieczorek等人，2013年）。我们产生了Arid 1b杂合子小鼠，这些小鼠表现出社会行为障碍、发声改变、焦虑样行为、神经解剖异常和生长障碍。在大脑中，Arid 1b单倍不足导致与神经精神疾病有关的SWI/SNF调节基因表达的变化。对可逆机制的关注确定了胰岛素样生长因子（IGF 1）缺乏，生长激素释放激素（GHRH）和生长激素（GH）补偿不足，ARID 1B患者的发现未得到充分重视。治疗上，生长激素补充剂能够纠正生长迟缓和肌肉无力。该模型在功能上验证了ARID 1B在人类疾病中的参与，并允许对与染色质重塑相关的神经发育疾病进行机械解剖。
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.