The disease progression mutant mice is affected of Mecp2 by the level of BDNF expression
The disease progression mutant mice is affected of Mecp2 by the level of BDNF expression
复制标题
DOI：
10.1016/j.neuron.2005.12.027
复制
发表时间：
2006-02-02
期刊：
影响因子：
16.2
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
--
作者：
Chang, QA;Khare, G;Jaenisch, R
MECP2基因的突变会导致瑞特综合征（RTT）。脑源性神经营养因子（Bdnf）是MeCP2的一个靶基因；然而，其在瑞特综合征发病机制中的作用尚不清楚。我们对脑源性神经营养因子条件性突变小鼠进行了与瑞特综合征相关的病理学检查，观察到脑源性神经营养因子的缺失导致脑体积变小、CA2神经元变小、肾小球变小以及具有特征性的后肢紧握表型。在Mecp2突变小鼠中，脑源性神经营养因子蛋白水平降低，并且在Mecp2突变体中删除Bdnf会导致瑞特综合征样症状更早出现。为了评估这种相互作用是否具有功能性以及潜在的治疗相关性，我们利用条件性Bdnf转基因增加了Mecp2突变大脑中的脑源性神经营养因子表达。脑源性神经营养因子的过表达延长了寿命，挽救了运动缺陷，并逆转了在Mecp2突变体中观察到的电生理缺陷。我们的研究结果为Mecp2和Bdnf之间的功能性相互作用提供了体内证据，并证明了脑源性神经营养因子表达/信号改变在瑞特综合征疾病进展中的生理意义。
Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.