Dysregulation of the SIRT1/OCT6 Axis Contributes to Environmental Stress-Induced Neural Induction Defects.
Dysregulation of the SIRT1/OCT6 Axis Contributes to Environmental Stress-Induced Neural Induction Defects.
复制标题
SIRT1/OCT6 轴失调导致环境压力诱发的神经感应缺陷
DOI：
10.1016/j.stemcr.2017.03.017
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发表时间：
2017-05-09
影响因子：
5.9
通讯作者：
Kang J
中科院分区：
文献类型：
--
作者：
Li G;Jiapaer Z;Weng R;Hui Y;Jia W;Xi J;Wang G;Zhu S;Zhang X;Feng D;Liu L;Zhang X;Kang J
环境应激是导致神经管畸形（NTDs）的神经诱导异常的核心原因。然而，环境应激引发的神经诱导缺陷的机制仍然未知。在这里，我们报告了一系列的环境压力，包括氧化应激，饥饿和DNA损伤，深刻激活SIRT 1，NAD+依赖性赖氨酸脱乙酰酶。小鼠胚胎和体外分化的胚胎干细胞（ESCs）的SIRT 1和OCT 6（一种关键的神经命运诱导剂）的表达之间呈负相关。活化的SIRT 1使OCT 6彻底脱乙酰化，触发OCT 6泛素化/降解级联反应，从而增加小鼠中NTD样表型的发生率或阻碍人类和小鼠ESC中的神经诱导。总之，我们的研究结果表明，早期暴露于环境压力导致SIRT 1/OCT 6轴的失调，并增加NTD的风险。环境应激在神经管发育过程中深刻激活SIRT 1激活SIRT 1使OCT 6脱乙酰并诱导其泛素化/降解SIRT 1/OCT 6轴与环境应激诱导的神经管缺陷有关SIRT 1/OCT 6轴参与正常神经管发育的早期阶段在这篇文章中，Kang及其同事证明了环境应激深刻激活SIRT 1，其进一步使OCT 6脱乙酰并触发OCT 6泛素化/降解级联反应。Oct 6特异性表达于外胚层和早期神经外胚层，是神经诱导所必需的。在体内和体外，环境应激触发的SIRT 1/OCT 6轴失调导致神经诱导缺陷和神经管缺陷样表型。
Environmental stresses are increasingly acknowledged as core causes of abnormal neural induction leading to neural tube defects (NTDs). However, the mechanism responsible for environmental stress-triggered neural induction defects remains unknown. Here, we report that a spectrum of environmental stresses, including oxidative stress, starvation, and DNA damage, profoundly activate SIRT1, an NAD+-dependent lysine deacetylase. Both mouse embryos and in vitro differentiated embryonic stem cells (ESCs) demonstrated a negative correlation between the expression of SIRT1 and that of OCT6, a key neural fate inducer. Activated SIRT1 radically deacetylates OCT6, triggers an OCT6 ubiquitination/degradation cascade, and consequently increases the incidence of NTD-like phenotypes in mice or hinders neural induction in both human and mouse ESCs. Together, our results suggest that early exposure to environmental stresses results in the dysregulation of the SIRT1/OCT6 axis and increases the risk of NTDs. Environmental stresses profoundly activate SIRT1 during neural tube development Activated SIRT1 deacetylates OCT6 and induces its ubiquitination/degradation SIRT1/OCT6 axis is related to environmental stress-induced neural tube defects SIRT1/OCT6 axis is involved in the early stage of normal neural tube development In this article, Kang and colleagues demonstrate that environmental stresses profoundly activate SIRT1, which further deacetylates OCT6 and triggers an OCT6 ubiquitination/degradation cascade. Oct6, specifically expressed in the epiblast and early neuroectoderm, is indispensable for neural induction. Environmental stress-triggered dysregulation of the SIRT1/OCT6 axis leads to neural induction defects and neural tube defect-like phenotypes both in vivo and in vitro.