Transcriptional changes and developmental abnormalities in a zebrafish model of myotonic dystrophy type 1.
Transcriptional changes and developmental abnormalities in a zebrafish model of myotonic dystrophy type 1.
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DOI：
10.1242/dmm.012427
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发表时间：
2014-01
影响因子：
4.3
通讯作者：
Dowling JJ
中科院分区：
文献类型：
--
作者：
Todd PK;Ackall FY;Hur J;Sharma K;Paulson HL;Dowling JJ
强直性肌营养不良I型（DM1）是一种多系统常染色体显性遗传疾病，由DMPK基因3′UTR的CTG重复序列扩增引起。重复序列的大小与发病年龄和疾病严重程度相关，大的重复序列导致与张力减退和智力残疾相关的先天性DM 1。在成人DM 1模型中，扩展的CUG重复序列导致RNA毒性功能获得，至少部分通过隔离特定的RNA剪接蛋白介导，最显著的是肌盲相关（MBNL）蛋白。然而，CUG RNA重复表达对早期发育过程的影响还没有得到很好的理解。为了更好地了解DM1的早期发育过程，我们利用斑马鱼作为模型系统。将含有（CUG）91重复序列的mRNA直接注射到单细胞胚胎中会在早期发育过程中诱导神经系统和肌肉的毒性。这些影响表现为异常形态，行为异常和广泛的转录变化，如cDNA微阵列分析所示。共注射斑马鱼mbnl2 RNA抑制（CUG）91 RNA毒性和逆转相关的行为和转录异常。总之，这些发现表明，外源性转录的CUG重复RNA的早期表达可以破坏正常的肌肉和神经系统发育，并为DM1研究提供了一个新的模型，适合小分子治疗的发展。
Myotonic dystrophy type I (DM1) is a multi-system, autosomal dominant disorder caused by expansion of a CTG repeat sequence in the 3′UTR of the DMPK gene. The size of the repeat sequence correlates with age at onset and disease severity, with large repeats leading to congenital forms of DM1 associated with hypotonia and intellectual disability. In models of adult DM1, expanded CUG repeats lead to an RNA toxic gain of function, mediated at least in part by sequestering specific RNA splicing proteins, most notably muscleblind-related (MBNL) proteins. However, the impact of CUG RNA repeat expression on early developmental processes is not well understood. To better understand early developmental processes in DM1, we utilized the zebrafish, Danio rerio, as a model system. Direct injection of (CUG)91 repeat-containing mRNA into single-cell embryos induces toxicity in the nervous system and muscle during early development. These effects manifest as abnormal morphology, behavioral abnormalities and broad transcriptional changes, as shown by cDNA microarray analysis. Co-injection of zebrafish mbnl2 RNA suppresses (CUG)91 RNA toxicity and reverses the associated behavioral and transcriptional abnormalities. Taken together, these findings suggest that early expression of exogenously transcribed CUG repeat RNA can disrupt normal muscle and nervous system development and provides a new model for DM1 research that is amenable to small-molecule therapeutic development.
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影响因子：
3.5
作者：
Gupta, Vandana;Kawahara, Genri;Beggs, Alan H.
通讯作者：
Beggs, Alan H.
影响因子：
4.5
作者：
Dowling, James J.;Vreede, Andrew P.;Low, Sean E.;Gibbs, Elizabeth M.;Kuwada, John Y.;Bonnemann, Carsten G.;Feldman, Eva L.
通讯作者：
Feldman, Eva L.
影响因子：
2.5
作者：
Cox, JA;Kucenas, S;Voigt, MM
通讯作者：
Voigt, MM
DOI：
10.1111/febs.12412
发表时间：
2013-09
期刊：
The FEBS journal
影响因子：
--
作者：
Gibbs EM;Horstick EJ;Dowling JJ
通讯作者：
Dowling JJ
影响因子：
21.3
作者：
Adereth, Y;Dammai, V;Hsu, T
通讯作者：
Hsu, T