Fxr1 knockout mice show a striated muscle phenotype:: implications for Fxr1p function in vivo
Fxr1 knockout mice show a striated muscle phenotype:: implications for Fxr1p function in vivo
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DOI：
10.1093/hmg/ddh150
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发表时间：
2004-07-01
影响因子：
3.5
通讯作者：
Nelson, DL
中科院分区：
文献类型：
--
作者：
Mientjes, EJ;Willemsen, R;Nelson, DL
FXR 1是FMR 1的两个已知同源物之一。FXR 1与FMR 1具有高度的序列同源性，还编码两个KH结构域和一个RGG结构域，赋予RNA结合能力。与FMRP相比，FXR 1 P在体内的功能知之甚少。Fmr 1和Fxr 2均存在小鼠敲除（KO）模型。为了研究Fxr 1在体内的功能，我们建立了Fxr 1 KO小鼠模型。纯合子Fxr 1 KO新生儿在出生后不久死亡，最可能是由于心脏或呼吸衰竭。对骨骼肌和心肌进行的组织化学分析显示，与野生型（WT）同窝仔相比，E19 Fxr 1新生儿的细胞架构和结构受到破坏。在WT E19骨骼肌和心肌中，Fxr 1 p定位于肌肉内的肋区。在E19 Fxr 1 KO同窝仔中，除了Fxr 1 p的缺失外，还发现costameric蛋白黏着斑蛋白、肌养蛋白和α-辅肌动蛋白是离域的。第二种小鼠模型（Fxr 1 +neo），其表达的Fxr 1 p水平相对于WT同窝小鼠显著降低，未显示Fxr 1科斯中观察到的新生儿致死表型，但确实显示肢体肌肉组织显著减少，寿命缩短至18周。这里提出的结果指向Fxr 1 p在肌肉mRNA转运/翻译控制中的作用，类似于在神经元细胞中观察到的Fmrp。
FXR1 is one of the two known homologues of FMR1. FXR1 shares a high degree of sequence homology with FMR1 and also encodes two KH domains and an RGG domain, conferring RNA-binding capabilities. In comparison with FMRP, very little is known about the function of FXR1P in vivo. Mouse knockout (KO) models exist for both Fmr1 and Fxr2. To study the function of Fxr1 in vivo, we generated an Fxr1 KO mouse model. Homozygous Fxr1 KO neonates die shortly after birth most likely due to cardiac or respiratory failure. Histochemical analyses carried out on both skeletal and cardiac muscles show a disruption of cellular architecture and structure in E19 Fxr1 neonates compared with wild-type (WT) littermates. In WT E19 skeletal and cardiac muscles, Fxr1p is localized to the costameric regions within the muscles. In E19 Fxr1 KO littermates, in addition to the absence of Fxr1p, costameric proteins vinculin, dystrophin and alpha-actinin were found to be delocalized. A second mouse model (Fxr1+neo), which expresses strongly reduced levels of Fxr1p relative to WT littermates, does not display the neonatal lethal phenotype seen in the Fxr1 KOs but does display a strongly reduced limb musculature and has a reduced life span of similar to18 weeks. The results presented here point towards a role for Fxr1p in muscle mRNA transport/translation control similar to that seen for Fmrp in neuronal cells.