Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities.
Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities.
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DOI：
10.1093/nar/gki338
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发表时间：
2005
影响因子：
14.9
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中科院分区：
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一个内含子六核苷酸UGCAUG已被证明在多种组织中对前体mRNA的组织特异性可变剪接的调控起着关键作用。脊椎动物Fox - 1已被证明通过其RNA识别基序（RRM）以高度序列特异性的方式与该元件结合。在哺乳动物中，至少有两个与Fox - 1相关的基因，即ataxin - 2结合蛋白1（A2BP1）/Fox - 1和Fxh/Rbm9，它们编码相同的RRM。在此，我们证明小鼠Fxh和A2BP1转录本都经历组织特异性可变剪接，产生大脑和肌肉特异的蛋白质异构体。这些组织特异性异构体的特征在于它们调节非肌肉肌球蛋白重链II - B前体mRNA中一个盒式外显子N30的神经细胞特异性可变剪接的能力，此前已证明该外显子是通过一个内含子远端下游增强子（IDDE）调控的。所有具有RRM的Fxh和A2BP1异构体都能够在体外通过UGCAUG元件与IDDE结合。然而，每种异构体在转染细胞中的剪接活性和核分布都表现出数量上的差异。所有Fxh异构体和A2BP1的一种大脑异构体都显示出主要的核定位。Fxh和A2BP1的大脑异构体比肌肉特异性异构体更有效地促进N30剪接。骨骼肌表达另外一些缺少部分RRM的异构体。这些异构体不能激活神经细胞特异性剪接，而且还能抑制依赖于UGCAUG的N30剪接。这些发现表明Fxh和A2BP1的组织特异性异构体在决定UGCAUG介导的可变剪接的组织特异性方面起着重要作用。
An intronic hexanucleotide UGCAUG has been shown to play a critical role in the regulation of tissue-specific alternative splicing of pre-mRNAs in a wide range of tissues. Vertebrate Fox-1 has been shown to bind to this element, in a highly sequence-specific manner, through its RNA recognition motif (RRM). In mammals, there are at least two Fox-1-related genes, ataxin-2 binding protein 1 (A2BP1)/Fox-1 and Fxh/Rbm9, which encode an identical RRM. Here, we demonstrate that both mouse Fxh and A2BP1 transcripts undergo tissue-specific alternative splicing, generating protein isoforms specific to brain and muscle. These tissue-specific isoforms are characterized for their abilities to regulate neural cell-specific alternative splicing of a cassette exon, N30, in the non-muscle myosin heavy chain II-B pre-mRNA, previously shown to be regulated through an intronic distal downstream enhancer (IDDE). All Fxh and A2BP1 isoforms with the RRM are capable of binding to the IDDE in vitro through the UGCAUG elements. Each isoform, however, shows quantitative differences in splicing activity and nuclear distribution in transfected cells. All Fxh isoforms and a brain isoform of A2BP1 show a predominant nuclear localization. Brain isoforms of both Fxh and A2BP1 promote N30 splicing much more efficiently than do the muscle-specific isoforms. Skeletal muscles express additional isoforms that lack a part of the RRM. These isoforms are incapable of activating neural cell-specific splicing and, moreover, can inhibit UGCAUG-dependent N30 splicing. These findings suggest that tissue-specific isoforms of Fxh and A2BP1 play an important role in determining tissue specificity of UGCAUG-mediated alternative splicing.