Enhanced dense core granule function and adrenal hypersecretion in a mouse model of Rett syndrome.
Enhanced dense core granule function and adrenal hypersecretion in a mouse model of Rett syndrome.
复制标题
雷特综合征小鼠模型中致密核心颗粒功能增强和肾上腺分泌过多。
DOI：
10.1111/j.1460-9568.2009.06858.x
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Katz,DavidM
中科院分区：
文献类型：
--
作者：
Ladas,Thomas;Chan,Shyue-An;Ogier,Michael;Smith,Corey;Katz,DavidM
Rett 综合征 (RTT) 是一种进行性发育障碍，由编码甲基 CpG 结合蛋白 2 (MeCP2)（一种转录调节蛋白）的基因发生功能丧失突变所致。 RTT 表型很复杂，包括严重的心肺异常、自主神经功能障碍和压力升高的行为症状。这些发现归因于脑干发育缺陷导致交感神经系统明显过度活跃。然而，尚未探讨外周交感肾上腺轴本身异常的可能性。本研究表明，与野生型对照相比，Mecp2null 小鼠的肾上腺髓质和交感神经节的儿茶酚胺含量显着降低。尽管如此，无效动物表现出显着较高的血浆肾上腺素水平，表明肾上腺嗜铬细胞中的分泌颗粒功能增强。事实上，我们发现Mecp2null嗜铬细胞表现出细胞自主的过度分泌表型，其特征是响应于电刺激的个体分泌颗粒融合事件的速度和大小显着增加。这些发现似乎表明分泌颗粒融合孔的加速形成和增强的扩张，导致儿茶酚胺释放增加。因此，我们的数据强调交感肾上腺轴中儿茶酚胺功能异常是 RTT 自主神经功能障碍的潜在来源。这些发现可能有助于解释 RTT 患者交感神经系统明显的“过度活跃”。
Rett syndrome (RTT) is a progressive developmental disorder resulting from loss‐of‐function mutations in the gene encoding methyl‐CpG‐binding protein 2 (MeCP2), a transcription regulatory protein. The RTT phenotype is complex and includes severe cardiorespiratory abnormalities, dysautonomia and behavioral symptoms of elevated stress. These findings have been attributed to an apparent hyperactivity of the sympathetic nervous system due to defects in brainstem development; however, the possibility that the peripheral sympathoadrenal axis itself is abnormal has not been explored. The present study demonstrates that the adrenal medulla and sympathetic ganglia ofMecp2null mice exhibit markedly reduced catecholamine content compared with wild‐type controls. Despite this, null animals exhibit significantly higher plasma epinephrine levels, suggesting enhanced secretory granule function in adrenal chromaffin cells. Indeed, we find thatMecp2null chromaffin cells exhibit a cell autonomous hypersecretory phenotype characterized by significant increases in the speed and size of individual secretory granule fusion events in response to electrical stimulation. These findings appear to indicate accelerated formation and enhanced dilation of the secretory granule fusion pore, resulting in elevated catecholamine release. Our data therefore highlight abnormal catecholamine function in the sympathoadrenal axis as a potential source of autonomic dysfunction in RTT. These findings may help to explain the apparent ‘overactivity’ of the sympathetic nervous system reported in patients with RTT.