MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function.
MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function.
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DOI：
10.7554/elife.83806
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发表时间：
2023-02-27
期刊：
影响因子：
7.7
通讯作者：
Zoghbi HY
中科院分区：
文献类型：
--
作者：
Bajikar SS;Anderson AG;Zhou J;Durham MA;Trostle AJ;Wan YW;Liu Z;Zoghbi HY
MeCP2的功能丧失和获得分别导致Rett综合征（RTT）和MECP2复制综合征（MDS）。MeCP2结合甲基胞嘧啶以微调大脑中的基因表达，但识别由MeCP2强烈调控的基因一直很困难。通过整合多个转录组学数据集，我们发现MeCP 2可以精细调节生长分化因子11（Gdf 11）。Gdf11在RTT小鼠模型中下调，相反，在MDS小鼠模型中上调。引人注目的是，遗传正常化Gdf11剂量水平改善了MDS小鼠模型中的几种行为缺陷。接下来，我们发现，仅仅丢失一个Gdf11拷贝就足以导致小鼠的多种神经行为缺陷，最明显的是多动症和学习记忆能力下降。这种学习和记忆的下降不是由于海马体中祖细胞增殖或数量的变化。最后，Gdf11的一个拷贝的丢失降低了小鼠的存活率，证实了它在衰老中的假定作用。我们的数据表明，Gdf11剂量对脑功能很重要。
Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.