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, receptormediated 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 LPAdependent 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.Lysophospholipids, such as lysophosphatidic acid (LPA) 4 and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs affect many biological processes, including neurogenesis, angiogenesis, would healing, immunity, and carcinogenesis through activation of specific G protein-coupled receptors (1-4).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.Neuron-glia interactions play an important role in many neurodevelopmental processes, including neurogenesis (14 -16), neuronal migration (17), axonal guidance (18 -22), myelination (23), synapse formation (24), and glial maturation (25)(26)(27)(28)(29)(30)(31). Astrocytes, the most abundant glial cell type, produce most of the extracellular matrix components and neurotrophic factors in the central nervous system that are involved in axonal growth (18,19,22,32), neuronal proliferation, survival, and stem cell fate determination (14,19,20,26,(33)(34)(35)(36)(37).Astrocytes have been shown to...