Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling
Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling
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DOI：
10.1073/pnas.1106129108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Chun, Jerold
中科院分区：
文献类型：
--
作者：
Herr, Keira Joann;Herr, Deron R.;Chun, Jerold
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还不完全清楚，但可能涉及大脑皮层层状组织的破坏。溶血磷脂酸（LPA）是一种生物活性脂质，能够通过六种同源G蛋白偶联受体LPA（1-6）中的一种或多种影响皮质，其中几种在胎儿神经祖细胞（NPC）中富集。在这里，我们报告，胎儿缺氧诱导皮质破坏通过增加LPA（1）信号，涉及定型效应的NPC：N-钙粘蛋白破坏，有丝分裂的NPC的位移，受损的神经元迁移，评估在体外和体内。重要的是，LPA（1）的遗传去除或药理学抑制可防止这些缺氧诱导现象的发生。缺氧通过选择性抑制G蛋白偶联受体激酶2的表达和激活包括G（α i）和Ras相关的C3肉毒杆菌毒素底物1在内的下游途径导致LPA（1）的过度激活。这些数据确定了刻板的和选择性的缺氧诱导的大脑皮质破坏需要LPA（1）信号，抑制它可以减少或预防疾病相关的后遗症，并可能使我们更接近胎儿缺氧诱导的CNS疾病和其他形式的缺氧损伤的治疗。
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, LPA(1-6), several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA(1) 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(1) prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA(1) through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including G(alpha i) and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA(1) 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.