Abstract
Lysophosphatidic acid (LPA) is a simple phospholipid derived from cell membranes that has extracellular signaling properties mediated by at least five G protein-coupled receptors referred to as LPA(1)-LPA(5). In the nervous system, receptor-mediated LPA signaling has been demonstrated to influence a range of cellular processes; however, an unaddressed aspect of LPA signaling is its potential to produce specific secondary effects, whereby LPA receptor-expressing cells exposed to, or "primed," by LPA may then act on other cells via distinct, yet LPA-initiated, mechanisms. In the present study, we examined cerebral cortical astrocytes as possible indirect mediators of the effects of LPA on developing cortical neurons. Cultured astrocytes express at least four LPA receptor subtypes, known as LPA(1)-LPA(4). Cerebral cortical astrocytes primed by LPA exposure were found to increase neuronal differentiation of cortical progenitor cells. Treatment of unprimed astrocyte-progenitor cocultures with conditioned medium derived from LPA-primed astrocytes yielded similar results, suggesting the involvement of an astrocyte-derived soluble factor induced by LPA. At least two LPA receptor subtypes are involved in LPA priming, since the priming effect was lost in astrocytes derived from LPA receptor double-null mice (LPA(1)((-/-))/LPA(2)((-/-))). Moreover, the loss of LPA-dependent differentiation in receptor double-null astrocytes could be rescued by retrovirally transduced expression of a single deleted receptor. These data demonstrate that receptor-mediated LPA signaling in astrocytes can induce LPA-dependent, indirect effects on neuronal differentiation.
Highlights
Lysophospholipids, such as lysophosphatidic acid (LPA)4 and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators
Characterization of LPA Receptor (LPAR) Gene Expression in Cerebral Cortical Astrocytes in Vitro—To investigate LPAR signaling effects on astrocytes, we examined actin stress fiber formation in cortical astrocytes, a well described phenomenon elicited by lysophospholipids [45, 46]
The major finding of the present study is that receptor-mediated LPA signaling through astrocytes can act indirectly to promote neuronal differentiation
Summary
Lysophospholipids, such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPA receptors are expressed by most neural cell types and are involved in several developmental processes within the nervous system, including normal brain development and function [2, 5, 6], growth and folding of the cerebral cortex [7], growth cone and process retraction (8 –10), cell survival [7, 11], cell migration [12], cell adhesion [13], and proliferation [2, 7] These observations underscore the importance of lipid signaling in normal and pathological nervous system development. We report that astrocytes primed by LPA increase neuronal differentiation, likely through a soluble factor, and that this activity is dependent on activation of defined LPA receptors expressed on astrocytes
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