Glycosphingolipid metabolic reprogramming drives neural differentiation
Glycosphingolipid metabolic reprogramming drives neural differentiation
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DOI：
10.15252/embj.201797674
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发表时间：
2018-04-03
期刊：
影响因子：
11.4
通讯作者：
D'Angelo, Giovanni
中科院分区：
文献类型：
--
作者：
Russo, Domenico;Della Ragione, Floriana;D'Angelo, Giovanni
神经发育是通过导致代谢重编程的分化事件完成的。鞘糖脂代谢在神经发育过程中被重新编程，从全球到神经节系列鞘糖脂生产的转换。鞘糖脂开关的失败会导致人类神经发育障碍，这表明鞘糖脂在这一过程中起着关键作用。然而，控制鞘糖脂开关的分子机制及其在神经发育中的功能尚不清楚。在这里，我们描述了一个控制鞘糖脂重编程和神经分化的独立电路。我们发现globo系列鞘糖脂抑制神经元基因表达的表观遗传调控因子AUTS2。反过来，AUTS2结合并激活第一种限速神经节苷脂产生酶GM3合成酶的启动子，从而促进神经节苷脂的合成。通过这种机制，globo-AUTS2轴在神经分化过程中控制鞘糖脂重编程和神经基因表达，这涉及到该回路在神经发育中的作用及其在神经病理中的缺陷。
Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo- to ganglio-series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self-contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo-series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate-limiting ganglioside-producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology.