Mutant Human Embryonic Stem Cells Reveal Neurite and Synapse Formation Defects in Type 1 Myotonic Dystrophy
Mutant Human Embryonic Stem Cells Reveal Neurite and Synapse Formation Defects in Type 1 Myotonic Dystrophy
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DOI：
10.1016/j.stem.2011.02.004
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发表时间：
2011-04-08
期刊：
影响因子：
23.9
通讯作者：
Martinat, Cecile
中科院分区：
文献类型：
--
作者：
Marteyn, Antoine;Maury, Yves;Martinat, Cecile
1型肌强直性营养不良（DM1）是一种影响多种器官的多系统疾病，包括中枢神经系统。通过使用携带DM1突变的人类胚胎干细胞衍生的神经元后代，我们已经确定了参与神经突形成和神经肌肉连接建立的基因的早期发育缺陷。差异基因表达谱和定量RT-PCR显示，在DM1神经细胞和DM1脑活检中，SLITRK家族的两个成员的表达降低。此外，DM1运动神经元/肌肉细胞共培养显示的改变与SLITRK基因在神经突生长、神经细胞发生和突触发生中的已知作用一致。挽救和敲低实验表明，功能缺陷可直接归因于SLITRK错表达。这些神经病理机制可能对与DM1相关的神经肌肉连接的功能改变具有临床意义。
Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting a variety of organs, including the central nervous system. By using neuronal progeny derived from human embryonic stem cells carrying the causal DM1 mutation, we have identified an early developmental defect in genes involved in neurite formation and the establishment of neuromuscular connections. Differential gene expression profiling and quantitative RT-PCR revealed decreased expression of two members of the SLITRK family in DM1 neural cells and in DM1 brain biopsies. In addition, DM1 motoneuron/muscle cell cocultures showed alterations that are consistent with the known role of SLITRK genes in neurite outgrowth, neuritogenesis, and synaptogenesis. Rescue and knockdown experiments suggested that the functional defects can be directly attributed to SLITRK misexpression. These neuropathological mechanisms may be clinically significant for the functional changes in neuromuscular connections associated with DM1.