LPA6 signaling as a modulator of oligodendrocyte differentiation and CNS myelination

脊椎动物中枢神经系统（CNS）髓鞘能够快速有效地传输信号

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.