Ronnett Gabriele V, Leopold Donald, Cai Xiaohe, Hoffbuhr Kristen C, Moses Linda, Hoffman Eric P, Naidu Sakkubai
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ann Neurol. 2003 Aug;54(2):206-18. doi: 10.1002/ana.10633.
Rett's Syndrome (RTT) is a neurodevelopmental disorder resulting from mutation in the mecp2 gene that encodes methyl CpG binding protein 2, a transcriptional repressor. Because this disease primarily affects neurons, tissue is not available during active disease. We used the olfactory system as a model to investigate abnormalities in neuronal development in RTT, because olfactory receptor neurons (ORNs) are replaced throughout life by ongoing postnatal neurogenesis. Thus, even in the adult, the olfactory epithelium contains neurons at various developmental stages. We obtained biopsies of nasal epithelium containing ORNs from RTT patients and age-matched controls to study the status of the neuronal population using antibodies to stage-specific developmental markers. There were no postprocedure complications. Compared with age-matched controls, there were far fewer mature ORNs, as defined by olfactory marker protein expression, and significantly greater numbers of immature neuron-specific tubulin-positive ORNs present. In RTT biopsies, olfactory marker protein-positive neurons displayed abnormal structure. These results suggest that dysfunction of MeCP2 results in decreased survival of mature ORNs with a compensatory increase in neurogenesis, or a failure of immature neurons to mature. Our study indicates that olfactory biopsies provide a method to study neuronal developmental diseases in adults and children.
雷特综合征（RTT）是一种神经发育障碍疾病，由编码甲基化CpG结合蛋白2（一种转录抑制因子）的mecp2基因突变引起。由于这种疾病主要影响神经元，在疾病活动期无法获取组织样本。我们以嗅觉系统为模型来研究雷特综合征中神经元发育的异常情况，因为嗅觉受体神经元（ORN）在出生后的整个生命过程中会通过持续的神经发生不断更新。因此，即使在成年个体中，嗅觉上皮也包含处于不同发育阶段的神经元。我们从雷特综合征患者和年龄匹配的对照者身上获取了含有ORN的鼻上皮活检样本，使用针对特定阶段发育标志物的抗体来研究神经元群体的状态。术后没有出现并发症。与年龄匹配的对照者相比，由嗅觉标记蛋白表达所定义的成熟ORN数量要少得多，而未成熟的神经元特异性微管蛋白阳性ORN数量则显著更多。在雷特综合征活检样本中，嗅觉标记蛋白阳性神经元呈现出异常结构。这些结果表明，MeCP2功能障碍导致成熟ORN存活率降低，同时神经发生代偿性增加，或者未成熟神经元无法成熟。我们的研究表明，嗅觉活检为研究成人和儿童的神经元发育疾病提供了一种方法。
