LPA6 signaling as a modulator of oligodendrocyte differentiation and CNS myelination

脊椎动物中枢神经系统(CNS)的髓鞘使信号能够沿 轴突，它为维持轴突的完整性提供代谢支持。有了这些功能，中枢神经系统髓鞘 鞘对神经回路功能起着至关重要的作用。因此，监管失调似乎并不令人惊讶。 调控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)在越来越多的骨肉瘤的病理生理学中起重要作用 神经系统疾病。然而，尽管OLG分化对于中枢神经系统功能至关重要， 调控这些事件的信号通路仍然知之甚少。在这种情况下，受体 由于对脂质信号分子的选择性，溶血磷脂酸(LPA)很早就被认为是 但LPA信号在调节OLG分化中的功能作用很大程度上 仍然默默无闻。产生LPA的主要途径之一是通过酶 溶血磷脂酶D(Lyso PLD)活性的胞外蛋白自体趋化蛋白(ATX)。通过我们之前的研究， 我们证实，抑制ATX的溶血性PLD活性可以减弱OLG的分化，因此提示 LPA受体信号在OLG分化中的调节作用到目前为止，有六个真正的LPA受体(LPA1-6 由Lpar1-6编码)已在哺乳动物中被识别。除了Lpar5，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。为了努力剖析这些人的个人角色 已知的LPA受体，我们的最新发现有点令人惊讶地指向负调节作用 通过LPA6发送信号。值得注意的是，LPA6受体的反应可以由膜- 通过膜相关脂酶H(LIPH)的酶活性产生的包埋型LPA，以及转录 分析表明，OLG，特别是在谱系的早期阶段，也表达Liph。总而言之，这些 观察结果支持这一中心假设，即LPA6信号作为一种负向调节器作用于 与OLG分化相关的转录程序，由此该信号事件很可能 主要由LIPH活动触发生成LPA。在拟议的研究中，我们将描述1)体内的 OLG来源的LPA6在调节发育的OLG分化中的作用，从而通过 条件性Lpar6基因敲除小鼠的建立和分析；2)LPA6和脂肪酶H在体外的作用 (LIPH)介导的LPA6在OLG分化中的激活作用 分化OLG的原代培养。综上所述，拟议的研究从概念上解决了 OLG分化和中枢神经系统髓鞘形成受复杂LPA信号调控的新观点 具有相反的，即正向和负向调制成分的网络。重要的是，有 越来越多的证据表明，LPA信号网络可能在特别是病理性疾病下调节失调 与炎症反应相关的中枢神经系统状况。

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.