Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes
Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes
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DOI：
10.1093/hmg/ddm128
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
--
作者：
Bi, Weimin;Yan, Jiong;Lupski, James R.
Smith-Magenis综合征（SMS）与17p11.2中类似的3.7 Mb常见缺失相关，并以其颅面和神经行为异常为特征。这种相互复制导致了与波托基-卢普斯基综合征（PLS）相关的dup（17）（p11.2p11.2），这是一种神经系统疾病，其特征包括自闭症。视黄酸诱导1（RAI 1）似乎是负责SMS和PLS的大多数临床特征。这些综合征的小鼠模型分别具有类似于2 Mb染色体工程缺失和复制，显示异常的运动活动和/或学习缺陷。为了确定RAI 1在SMS神经行为特征中的贡献，我们对Rail突变小鼠和具有类似于590 kb的小缺失的Df（11）17-1/+小鼠进行了一系列行为测试。小缺失的小鼠像大缺失的小鼠一样活动减退，它们也表现出学习缺陷。Rai 1 +/-小鼠表现出正常的运动活动。然而，他们有一个异常的脑电图与明显的癫痫发作中观察到的一个子集的小鼠。少数存活的Rai 1-/-小鼠表现出更严重的神经行为异常，包括后肢紧握，明显的癫痫发作，运动障碍和上下文和音调依赖性学习缺陷。Rai 1 +/-小鼠的X-gal染色表明Rail主要在海马和小脑的神经元中表达。我们的研究结果表明，铁路是一个关键的基因在中枢神经系统中发挥作用的剂量敏感的方式和神经行为表型被修改的调节器（S）在类似的590 kb的基因组间隔，其中的主要修改器影响颅面神经反射驻留。
Smith-Magenis syndrome (SMS) is associated with an similar to 3.7 Mb common deletion in 17p11.2 and characterized by its craniofacial and neurobehavioral abnormalities. The reciprocal duplication leads to dup(17)(p11.2p11.2) associated with the Potocki-Lupski syndrome (PLS), a neurological disorder whose features include autism. Retinoic acid induced 1 (RAI1) appears to be responsible for the majority of clinical features in both SMS and PLS. Mouse models of these syndromes harboring an similar to 2 Mb chromosome engineered deletion and duplication, respectively, displayed abnormal locomotor activity and/or learning deficits. To determine the contribution of RAI1 in the neurobehavioral traits in SMS, we performed a battery of behavioral tests on Rail mutant mice and the Df(11)17-1/+ mice that have a small deletion of similar to 590 kb. The mice with the small deletion were hypoactive like the large deletion mice and they also showed learning deficits. The Rai1+/- mice exhibited normal locomotor activity. However, they had an abnormal electroencephalogram with overt seizure observed in a subset of mice. The few surviving Rai1 -/- mice displayed more severe neurobehavioral abnormalities including hind limb clasping, overt seizures, motor impairment and context- and tone-dependant learning deficits. X-gal staining of the Rai1 +/- mice suggests that Rail is predominantly expressed in neurons of the hippocampus and the cerebellum. Our results suggest that Rail is a critical gene in the central nervous system functioning in a dosage sensitive manner and that the neurobehavioral phenotype is modified by regulator(s) in the similar to 590 kb genomic interval, wherein the major modifier affecting the craniofacial penetrance resides.