Lysophosphatidic Acid can Support the Formation of Membranous Structures and an Increase in MBP mRNA Levels in Differentiating Oligodendrocytes

Abstract

During development, differentiating oligodendrocytes progress in distinct maturation steps from premyelinating to myelinating cells. Such maturing oligodendrocytes express both receptors mediating signaling via extracellular lysophosphatidic acid (LPA) and the major enzyme generating extracellular LPA, namely phosphodiesterase-Iα/autotaxin (PD-Iα/ATX). However, the biological role of extracellular LPA during the maturation of differentiating oligodendrocytes is currently unclear. Here, we demonstrate that application of exogenous LPA induced an increase in the area occupied by the oligodendrocytes' process network, but only when PD-Iα/ATX expression was down-regulated. This increase in network area was caused primarily by the formation of membranous structures. In addition, LPA increased the number of cells positive for myelin basic protein (MBP). This effect was associated by an increase in the mRNA levels coding for MBP but not myelin oligodendrocyte glycoprotein (MOG). Taken together, these data suggest that LPA may play a crucial role in regulating the later stages of oligodendrocyte maturation.

Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex

“…As reported previously, LPA 1 expression is correlated largely with the expression of myelin proteins, suggesting that the protein plays an important role in myelination (Allard et al 1998;Weiner et al 1998;Möller et al 1999;Handford et al 2001;Cervera et al 2002), which is supported by pharmacological evidence (Möller et al 1999;Stankoff et al 2002;Dawson et al 2003;Matsushita et al 2005;Nogaroli et al 2009). However, with the exception of studies (Contos et al 2000) demonstrating a minor increase in apoptosis in Schwann cells from the original LPA 1 -null mice, there are limited data and no in vivo evidence to support a role for LPA 1 in this function.…”

“…PLP, unlike MBP or CNPase, is synthesized in the RER, is subsequently transported via vesicles through the Golgi apparatus (GA), and is sorted to the plasma membrane, where the translated protein is inserted into myelin rafts (Colman et al 1982;Trapp et al 1987). Based on the cell count data and the suggested LPA-mediated effect on the oligodendrocyte cytoskeletal rearrangements involved in the membrane sheath formation (Nogaroli et al 2009), a reasonable hypothesis is that LPA 1 signaling plays a significant role in PLP transport; therefore, we investigated the stage along the pathway in which PLP was retained in the null oligodendrocytes. Double-immunofluorescence staining was performed to investigate PLP protein localization relative to the following markers in each cell compartment: (1) protein disulfide isomerase (PDI), an abundant endoplasmic reticulum chaperone protein that catalyzes disulfide-bond breakage and formation and is normally used as an RER marker (Wang 1998); (2) Golgi phosphoprotein (Golph4), a transmembrane protein localized to the cis-Golgi cisternae and a marker of early Golgi vesicle trafficking (Linstedt et al 1997); and (3) Lamp1, a type-I transmembrane glycoprotein that is localized primarily in lysosomes and late endosomes (Rohrer et al 1996), based on the observation that newly synthesized molecules are typically transported from the trans-Golgi network directly to the endosomes and, subsequently, to the lysosomes.…”

“…A role in the regulation of cortical myelination has been suggested for the LPA 1 receptor because of its expression in postnatal mature oligodendrocytes in association with the onset of myelination in the brain (Allard et al 1998;Weiner et al 1998;Möller et al 1999;Handford et al 2001;Cervera et al 2002;Yu et al 2004). The pharmacological response to LPA is apparently restricted to newly differentiated nonmyelinating and differentiating oligodendrocytes, affecting the formation of processes (Möller et al 1999;Dawson et al 2003) and the later stages of maturation (Matsushita et al 2005;Nogaroli et al 2009), but not the genuine precursors or mature oligodendrocytes (Stankoff et al 2002). It is precisely during this period that differentiating cortical oligodendrocytes exhibit activity of secreted endogenous autotaxin, the enzyme that generates extracellular LPA (Fox et al 2003;Dennis et al 2008;Nogaroli et al 2009).…”

“…The pharmacological response to LPA is apparently restricted to newly differentiated nonmyelinating and differentiating oligodendrocytes, affecting the formation of processes (Möller et al 1999;Dawson et al 2003) and the later stages of maturation (Matsushita et al 2005;Nogaroli et al 2009), but not the genuine precursors or mature oligodendrocytes (Stankoff et al 2002). It is precisely during this period that differentiating cortical oligodendrocytes exhibit activity of secreted endogenous autotaxin, the enzyme that generates extracellular LPA (Fox et al 2003;Dennis et al 2008;Nogaroli et al 2009). However, in addition to the responsiveness of exogenous LPA, further studies will be needed to demonstrate the in vivo function of LPA in the cortical myelination.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…However, both the rat OL precursor cell line CG-4 and freshly isolated precursors respond via Rho-ROCK cell rounding upon LPA exposure, in contrast to differentiated OLs (130). Similarly, LPA increases the network area of dendritic processes and MBP expression in differentiating OLs (131). Therefore, LPA may regulate OL function in a maturation stage-specifi c manner.…”