Altered Gene Expression of Thyroid Hormone Transporters and Deiodinases in iPS MeCP2-Knockout Cells-Derived Neurons
Altered Gene Expression of Thyroid Hormone Transporters and Deiodinases in iPS MeCP2-Knockout Cells-Derived Neurons
复制标题
DOI：
10.1007/s12035-019-01645-2
复制
发表时间：
2019-12-01
影响因子：
5.1
通讯作者：
Giannocco, Gisele
中科院分区：
文献类型：
--
作者：
de Souza, Janaina Sena;Ferreira, Divino Romao;Giannocco, Gisele
MeCP 2是一个X连锁基因;它的突变导致Rett综合征（RTT），这是一种严重的神经发育障碍，主要影响女孩。作为一种转录因子，MeCP 2蛋白能够调节几种与甲状腺相关的基因，如甲状腺激素（TH），已知其在中枢神经系统（CNS）的发育中起重要作用。虽然只有少数研究将RTT和TH相关联，但TH缺陷可通过触发成年期的功能缺陷而导致神经失调。在这里，我们使用人类诱导的多能干细胞（iPSC）来产生MeCP 2敲除的神经元祖细胞和成年神经元。使用这种细胞模型，我们研究了与TH稳态相关的基因的表达，如TH转运蛋白（LAT 1，LAT 2，MCT 8，MCT 10和OATP 4A 1）和脱碘酶（DIO 1，2和3）。然后，我们用TH处理神经细胞，并分析了与神经发育和功能维持相关的几个基因的表达。我们的研究结果表明，几个TH相关基因，如脱碘酶，在RTT样品相比，WT细胞改变。此外，用TH处理神经细胞增加RTT细胞中MAP 2和突触蛋白-1的表达量。我们的工作提供了证据，TH稳态在RTT衍生的神经细胞，这可能是一个重要的因素，有助于在这种综合征的神经发育表型的不平衡，并可以引导我们更好地了解其他神经发育疾病。
MeCP2 is an X-linked gene; its mutation causes Rett Syndrome (RTT), a severe neurodevelopmental disability that affects mainly girls. Acting as a transcription factor, the MeCP2 protein is able to regulate several hormone-related genes, such as the thyroid hormones (TH), which are known to play an important role in the development of the central nervous system (CNS). Although only a few studies have associated RTT and TH, TH deficit can lead to neurological deregulation by triggering functional deficiencies during adulthood. Here, we used human-induced pluripotent stem cell (iPSC) to generate MeCP2-knockout neuronal progenitor cells and adult neurons. Using this cellular model, we then investigated the expression of genes associated with TH homeostasis, such as the TH transporters (LAT1, LAT2, MCT8, MCT10, and OATP4A1) and deiodinases (DIO1, 2, and 3). Then, we treated the neural cells with THs and analyzed the expression of several genes related to neurodevelopment and functional maintenance. Our results showed that several TH-related genes, such as deiodinases, are altered in RTT samples when compared to WT cells. Moreover, the treatment of the neural cells with THs increased the amount of MAP2 and synapsin-1 expression in RTT cells. Our work provided evidences that TH homeostasis is compromised in RTT-derived neural cells, which could be an important factor to contribute to the imbalance in the neurodevelopmental phenotype presented in this syndrome and can lead us to better understand other neurodevelopmental diseases.