Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death
Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death
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DOI：
10.7554/elifel1627
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发表时间：
2016-02-08
期刊：
影响因子：
7.7
通讯作者：
Marmigere, Frederic
中科院分区：
文献类型：
--
作者：
Bouilloux, Fabrice;Thireau, Jerome;Marmigere, Frederic
虽然心血管事件和心源性猝死（SCD）是一般人群中过早死亡的主要原因之一，但在许多情况下，其原因仍然不明。全基因组关联研究已将Meis1确定为SCD的风险因素。我们报告说，Meis1在小鼠神经嵴失活导致改变交感神经迷走神经调节的心脏节律性的成人的变时性功能不全和心脏传导缺陷，从而增加了对SCD的易感性。我们证明，Meis1是交感神经靶区神经支配的主要调节因子，Meis1缺陷的交感神经元从胚胎早期到围产期通过凋亡死亡。此外，我们发现Meisl调节内体机制所必需的关键分子的转录。因此，Rab5（+）内体的运输在Meis 1失活的交感神经元中严重改变。这些结果表明，Meisl相互作用的各种营养因子信号通路在有丝分裂后神经元分化。
Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meisl regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5(+) endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meisl interacts with various trophic factors signaling pathways during postmitotic neurons differentiation.