LPA6 signaling as a modulator of oligodendrocyte differentiation and CNS myelination

LPA6 信号作为少突胶质细胞分化和 CNS 髓鞘形成的调节剂

• 批准号: 10288115
• 负责人: BABETTE FUSS
• 金额: $ 41.59万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288115
• 关键词: Acids; Address; Attenuated; Axon; Brain; Cells; Complex; Demyelinating Diseases; Development; Down-Regulation; Ensure; Event; Extracellular Protein; Functional disorder; G-Protein-Coupled Receptors; Gatekeeping; Gene Expression Profiling; Gene Silencing; Generations; Genetic Transcription; In Vitro; Individual; Inflammatory; Inflammatory Response; Knockout Mice; Ligands; Lipase; Lipids; Lysophosphatidic Acid Receptors; Lysophospholipase; Major Depressive Disorder; Mammals; Mediating; Membrane; Metabolic; Modeling; Multiple Sclerosis; Myelin Sheath; Nervous System Physiology; Neuraxis; Oligodendroglia; Pathologic; Pathway interactions; Play; Rattus; Receptor Signaling; Regulation; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Source; Substance Use Disorder; System; Transcriptional Regulation; Up-Regulation; alcohol use disorder; attenuation; in vivo; lysophosphatidic acid; membrane activity; myelination; nervous system disorder; neuronal circuitry; novel; oligodendrocyte lineage; prevent; programs; receptor; response; role model

The vertebrate central nervous system (CNS) myelin sheath enables fast and efficient signal propagation along axons, and it provides metabolic support for maintaining axonal integrity. With these features, the CNS myelin sheath critically contributes to neuronal circuitry function. Thus, it may not appear surprising that dysregulation of the transcriptional program governing the differentiation of the myelinating cells of the CNS, namely oligodendrocytes (OLGs), emerges as significant contributor to the pathophysiology of an increasing number of neurological diseases. Despite the critical importance of OLG differentiation for CNS function, however, the signaling pathways regulating these events are still only poorly understood. In this context, receptors with selectivity for the lipid signaling molecule lysophosphatidic acid (LPA) have long been known to be expressed by OLGs but the functional roles of LPA signaling in regulating OLG differentiation have largely remained obscure. One of the major pathways by which LPA is generated is via the enzymatic lysophospholipase D (lyso PLD) activity of the extracellular protein autotaxin (ATX). Through our previous studies, we established that inhibition of ATX’s lysoPLD activity attenuates OLG differentiation, thus suggesting a positive modulatory role of LPA receptor signaling in OLG differentiation. To date, six bona fide LPA receptors (LPA1-6 encoded by Lpar1-6) have been recognized in mammals. With the exception of Lpar5, all of these receptors are, at least to some extent, expressed by cells of the OLG lineage. In an effort to dissect the individual roles of the known LPA receptors, our most recent findings point, somewhat surprisingly, toward a negative modulatory role of signaling via LPA6. Notably, it has been shown that LPA6 receptor responses can be triggered by membrane- embedded LPA generated via the enzymatic activity of membrane-associated Lipase H (LIPH), and transcriptional profiling reveals that OLGs, especially at the earlier stages of the lineage, also express Liph. Collectively, these observations support the central hypothesis that LPA6 signaling functions as a negative modulator of the transcriptional program associated with OLG differentiation, whereby this signaling event is likely triggered primarily by LIPH activity generated LPA. In the proposed studies, we will characterize 1) in vivo the role of OLG-derived LPA6 in modulating developmental OLG differentiation and, thereby, CNS myelination via the generation and analysis of conditional Lpar6 knockout mice, and 2) in vitro the role of LPA6 and Lipase H (LIPH)-mediated LPA6 activation in OLG differentiation via the use of a well-established system of rat-derived primary cultures of differentiating OLGs. Taken together, the proposed studies address the conceptually novel idea that OLG differentiation and CNS myelination are regulated by a complex LPA signaling network with opposing, i.e. positive and negative modulatory, components. Importantly, there is increasing evidence that the LPA signaling network may be dysregulated under especially those pathological CNS conditions that are associated with inflammatory responses.

脊椎动物中枢神经系统（CNS）髓鞘使得信号能够沿着快速且有效地传播 轴突，并且它为维持轴突完整性提供代谢支持。有了这些特征， 鞘对神经元电路功能有重要贡献。因此，这可能并不奇怪，失调， 控制中枢神经系统髓鞘细胞分化的转录程序，即 少突胶质细胞（OLG），出现作为显着贡献者的病理生理学越来越多的 神经系统疾病尽管OLG分化对CNS功能至关重要，然而， 调节这些事件的信号通路仍然知之甚少。在这种情况下，受体 溶血磷脂酸（LPA）对脂质信号分子具有选择性， 但是LPA信号转导在调节OLG分化中的功能作用在很大程度上已经被证实。 仍然模糊。LPA产生的主要途径之一是通过酶促降解， 溶血磷脂酶D（lyso PLD）活性的细胞外蛋白自分泌运动因子（ATX）。通过我们以前的研究， 我们证实，抑制ATX的lysoPLD活性会减弱OLG的分化，因此提示了对OLG的正向调节作用。 LPA受体信号传导在OLG分化中的调节作用。迄今为止，六种真正的LPA受体（LPA 1 -6 由Lpar 1 -6编码）已经在哺乳动物中被识别。除了Lpar 5之外，所有这些受体都是， 至少在某种程度上由OLG谱系的细胞表达。为了剖析个人角色， 尽管已知LPA受体，但我们最近的发现有点令人惊讶地指向负调节作用， 通过LPA 6发送信号。值得注意的是，已经表明LPA 6受体反应可以由膜-细胞反应器触发。 通过膜相关脂肪酶H（LIPH）的酶活性产生的嵌入式LPA，以及转录 谱分析揭示OLG，特别是在谱系的早期阶段，也表达Liph。总的来说，这些 观察结果支持中心假设，即LPA 6信号传导作为一种负调节剂， 与OLG分化相关的转录程序，从而该信号事件可能是 主要由LIPH活动引发LPA。在拟议的研究中，我们将表征1）体内 OLG衍生的LPA 6在调节发育OLG分化中的作用，从而通过 条件性Lpar 6敲除小鼠的产生和分析，以及2）LPA 6和脂肪酶H在体外的作用 在OLG分化中，通过使用完善的大鼠来源的LIPH（LIPH）介导的LPA 6活化系统， 分化OLG的原代培养物。总的来说，拟议的研究从概念上解决了 OLG分化和CNS髓鞘形成受复杂LPA信号调节的新观点 网络具有相反的，即积极和消极的调节，组件。重要的是 越来越多的证据表明，LPA信号网络可能在特别是那些病理性的 与炎症反应相关的CNS疾病。