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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA) signaling
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Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA) signaling

机译：刻板印象的胎儿大脑紊乱是由缺氧引起的，需要溶血磷脂酸受体1（LPA）信号传导

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摘要

Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia, and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA1-6, several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA1 signaling involving stereotyped effects on NPCs: N-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo. Importantly, genetic removal or pharmacological inhibition, of LPA, prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overac-tivation of LPA, through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including Gα1and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA, signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury.
机译：胎儿缺氧是一种常见的危险因素，与一系列中枢神经系统疾病有关，包括癫痫，精神分裂症和自闭症。缺氧可能损害发育中的大脑的细胞和分子机制尚不完全清楚，但可能涉及破坏大脑皮层的层状组织。溶血磷脂酸（LPA）是一种生物活性脂质，能够通过六个关联的G蛋白偶联受体LPA1-6中的一个或多个受到皮层影响，其中一些富含胎儿神经祖细胞（NPC）。在这里，我们报道胎儿缺氧通过增加LPA1信号传导而引起皮层破坏，其中LPA1信号涉及对NPC的定型作用：N-钙黏着蛋白破坏，有丝分裂NPC的置换和受损的神经元迁移，如体外和体内评估。重要的是，LPA的遗传去除或药理抑制作用阻止了这些缺氧诱导的现象的发生。低氧通过选择性抑制G蛋白偶联受体激酶2的表达和激活包括Gα1和与Ras相关的C3肉毒杆菌毒素底物1在内的下游途径而导致LPA的过度活跃。这些数据确定了定型和选择性低氧诱导的大脑皮层破坏的必要性。 LPA，信号传导，其抑制作用可以减少或预防与疾病相关的后遗症，并可能使我们更接近于胎儿缺氧引起的CNS疾病和可能的其他形式的缺氧性损伤的治疗。

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