Knockout mouse model for Fxr2:: a model for mental retardation
Knockout mouse model for Fxr2:: a model for mental retardation
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DOI：
10.1093/hmg/11.5.487
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发表时间：
2002-03-01
影响因子：
3.5
通讯作者：
Oostra, BA
中科院分区：
文献类型：
--
作者：
Bontekoe, CJM;McIlwain, KL;Oostra, BA
脆性X综合征是一种常见的精神发育迟滞形式，由缺乏FMR1蛋白（FMRP）引起。Fmr1基因敲除小鼠表现出与人类相似的表型，如巨睾症和行为异常。已经鉴定了FMRP的两个同源物，FXR1P和FXR2P。这些蛋白质显示出高度的序列相似性，包括FMRP中鉴定的所有功能结构域，如RNA结合结构域。它们在组织分布上与FMRP重叠。三种FXR蛋白之间的相互作用也已被描述。FXR2P与FMRP一样，在脑和睾丸中高表达。为了研究FXR2P的功能，我们建立了FXR 2基因敲除小鼠模型。基因敲除小鼠和野生型小鼠在脑和睾丸中没有发现病理学差异。鉴于脆性X染色体患者的行为表型和先前报道的Fmr1敲除小鼠的表型，我们使用行为测试组合对Fxr2敲除表型进行了全面评估。Fxr2基因敲除小鼠在旷场测试中表现出过度活跃（即移动距离更远，移动时间更长，移动速度更快），在转棒测试中表现出受损，前脉冲抑制水平降低，表现出较少的情境条件性恐惧，在Morris水任务中定位隐藏平台时受损，对热刺激不太敏感。有趣的是，在Fxr2基因敲除小鼠中有一些行为表型与在Fmr1基因敲除小鼠中观察到的表型相似，但也有一些不同的行为异常仅在Fxr2突变小鼠中观察到。这些发现暗示了Fxr2在中枢神经系统功能中的作用。
Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Fmr1 knockout mice exhibit a phenotype with some similarities to humans, such as macro-orchidism and behavioral abnormalities. Two homologs of FMRP have been identified, FXR1P and FXR2P. These proteins show high sequence similarity, including all functional domains identified in FMRP, such as RNA binding domains. They have an overlap in tissue distribution to that of FMRP. Interactions between the three FXR proteins have also been described. FXR2P shows high expression in brain and testis, like FMRP. To study the function of FXR2P, we generated an Fxr2 knockout mouse model. No pathological differences between knockout and wild-type mice were found in brain or testis. Given the behavioral phenotype in fragile X patients and the phenotype previously reported for the Fmr1 knockout mouse, we performed a thorough evaluation of the Fxr2 knockout phenotype using a behavioral test battery. Fxr2 knockout mice were hyperactive (i.e. traveled a greater distance, spent more time moving and moved faster) in the open-field test, impaired on the rotarod test, had reduced levels of prepulse inhibition, displayed less contextual conditioned fear, impaired at locating the hidden platform in the Morris water task and were less sensitive to a heat stimulus. Interestingly, there are some behavioral phenotypes in Fxr2 knockout mice which are similar to those observed in Fmr1 knockout mice, but there are also some different behavioral abnormalities that are only observed in the Fxr2 mutant mice. The findings implicate a role for Fxr2 in central nervous system function.