Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model.
Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model.
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DOI：
10.1016/j.nbd.2022.105636
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发表时间：
2022-04
影响因子：
6.1
通讯作者：
MacDonald JL
中科院分区：
文献类型：
--
作者：
Ribeiro MC;MacDonald JL
Rett综合征（RTT）是一种由转录调节因子MECP2突变引起的x连锁神经系统疾病。Mecp2功能缺失导致许多细胞通路的破坏，包括NF-κB通路的异常激活。从基因上减弱mecp2缺失小鼠的NF-κB通路可改善RTT的标志性表型，包括降低树突复杂性，这就提出了NF-κB通路抑制剂是否可以为RTT提供治疗途径的问题。维生素D是一种已知的NF-κB信号传导抑制剂；此外，维生素D缺乏症在RTT患者和雄性mecp2缺失小鼠中普遍存在。我们之前的研究表明，维生素D可以在体外修复异常的NF-κB活性和减少mecp2缺失的皮质神经元的神经突生长，并且在体内，补充维生素D可以修复雄性半合子mecp2缺失小鼠和雌性杂合小鼠的新皮质投影神经元树突复杂性和体细胞大小的降低。在这里，我们已经确定了200多个基因在Mecp2+/−皮层中的表达失调是由膳食维生素D调节的。补充维生素D而正常化的基因与树突复杂性、突触和神经元突起有关，这表明它们的表达的恢复可能是神经元形态恢复的基础。此外，Mecp2+/−小鼠体内维生素D合成途径的稳态被破坏，Mecp2+/−小鼠的运动和焦虑样行为表型与循环维生素D水平相关。因此，我们的数据表明维生素D可以调节RTT的病理，补充维生素D可以为RTT提供一种简单而经济的部分治疗方法。
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the transcriptional regulator MECP2. Mecp2 loss-of-function leads to the disruption of many cellular pathways, including aberrant activation of the NF-κB pathway. Genetically attenuating the NF-κB pathway in Mecp2-null mice ameliorates hallmark phenotypes of RTT, including reduced dendritic complexity, raising the question of whether NF-κB pathway inhibitors could provide a therapeutic avenue for RTT. Vitamin D is a known inhibitor of NF-κB signaling; further, vitamin D deficiency is prevalent in RTT patients and male Mecp2-null mice. We previously demonstrated that vitamin D rescues the aberrant NF-κB activity and reduced neurite outgrowth of Mecp2-knockdown cortical neurons in vitro, and that dietary vitamin D supplementation rescues decreased dendritic complexity and soma size of neocortical projection neurons in both male hemizygous Mecp2-null and female heterozygous mice in vivo. Here, we have identified over 200 genes whose dysregulated expression in the Mecp2+/− cortex is modulated by dietary vitamin D. Genes normalized with vitamin D supplementation are involved in dendritic complexity, synapses, and neuronal projections, suggesting that the rescue of their expression could underpin the rescue of neuronal morphology. Further, there is a disruption in the homeostasis of the vitamin D synthesis pathway in Mecp2+/− mice, and motor and anxiety-like behavioral phenotypes in Mecp2+/− mice correlate with circulating vitamin D levels. Thus, our data indicate that vitamin D modulates RTT pathology and its supplementation could provide a simple and cost-effective partial therapeutic for RTT.
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影响因子：
4.9
作者：
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