Dual Regulation of Actin Rearrangement through Lysophosphatidic Acid Receptor in Neuroblast Cell Lines: Actin Depolymerization by Ca²⁺-α-Actinin and Polymerization by Rho

Abstract

Lysophosphatidic acid (LPA) is a potent lipid mediator with actions on many cell types. Morphological changes involving actin polymerization are mediated by at least two cognate G protein-coupled receptors, LPA 1 /EDG-2 or LPA 2 /EDG-4. Herein, we show that LPA can also induce actin depolymerization preceding actin polymerization within single TR mouse immortalized neuroblasts. Actin depolymerization resulted in immediate loss of membrane ruffling, whereas actin polymerization resulted in process retraction. Each pathway was found to be independent: depolymerization mediated by intracellular calcium mobilization, and ␣-actinin activity and polymerization mediated by the activation of the small Rho GTPase. ␣-Actininmediated depolymerization seems to be involved in growth cone collapse of primary neurons, indicating a physiological significance of LPA-induced actin depolymerization. Further evidence for dual regulation of actin rearrangement was found by heterologous retroviral transduction of either lpa 1 or lpa 2 in B103 cells that neither express LPA receptors nor respond to LPA, to confer both forms of LPA-induced actin rearrangements. These results suggest that diverging intracellular signals from a single type of LPA receptor could regulate actin depolymerization, as well as polymerization, within a single cell. This dual actin rearrangement may play a novel, important role in regulation of the neuronal morphology and motility during brain development.

Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) Lysophosphatidic Acid Receptor Knockout Mice: Signaling Deficits without Obvious Phenotypic Abnormality Attributable to lpa2

“…However, while the initial hypotheses regarding LPA signaling in brain development were tested in a general sense (i.e., proliferation and nuclear movement of cerebral cortical progenitor cells), we did not examine more specific effects or other potential roles for LPA, which are likely operative, based on other studies (21,23). LPA has also been hypothesized to influence wound healing by stimulating fibroblasts to close cutaneous wounds and possibly by attracting immune system cells to the injury site (6,16).…”

“…In embryonic cerebral cortex, for example, LPA is thought to mediate numerous aspects of progenitor behavior, including proliferation and cell cycle-associated morphological changes involving process retraction and nuclear movement (19,21,23,24). In general, however, hypotheses regarding the role of LPA in cerebral cortex development have been difficult to assess due to the lack of LPA agonists and antagonists specific to each LPA receptor.…”

Lysophosphatidic acid signaling controls cortical actin assembly and cytoarchitecture in Xenopus embryos

“…LPA-mediated signaling has been implicated in a wide range of cell behavior, including proliferation, survival, motility, cell shape and differentiation (Anliker and Chun, 2004;Fukushima et al, 2002;Tigyi, 2001;Ye et al, 2002). Targeted mutation of LPA receptors in the mouse has shown that LPA signaling is required for normal development (Contos et al, 2000;Contos et al, 2002).…”

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

“…To determine the role of G proteins in the development of CNS, we examined the effect of agonists that are bound to GPCRs on neuronal migration. Fukushima et al (28,29) demonstrated that lysophosphatidic acid (LPA) regulates cortical neuroblast morphology and induces cluster compaction of the neuroblast cell line. They also reported that LPA inhibits neuronal migration in explant cultures and wholebrain cultures.…”