VENTRICULAR ZONE GENE-1 (VZG-1) ENCODES A LYSOPHOSPHATIDIC ACID RECEPTOR EXPRESSED IN NEUROGENIC REGIONS OF THE DEVELOPING CEREBRAL-CORTEX

Neocortical neuroblast cell lines were used to clone G-protein-coupled receptor (GPCR) genes to study signaling mechanisms regulating cortic al neurogenesis. One putative GPCR gene displayed an in situ expressio n pattern enriched in cortical neurogenic regions and was therefore na med ventricular zone gene-1 (vzg-1). The vzg-1 cDNA hybridized to a 3. 8-kb mRNA transcript and encoded a protein with a predicted molecular mass of 41-42 kD, confirmed by Western blot analysis. To assess its fu nction, vzg-1 was overexpressed in a cell line from which it was clone d, inducing serum-dependent ''cell rounding.'' Lysophosphatidic acid ( LPA), a bioactive lipid present in high concentrations in serum, repro duced the effect seen with serum alone, Morphological responses to oth er related phospholipids or to thrombin, another agent that induces ce ll rounding through a GPCR, were not observed in vzg-1 overexpressing cells. Vzg-1 overexpression decreased the EC(50) of both cell rounding and G(i) activation in response to LPA. Pertussis toxin treatment inh ibited vzg-1-dependent LPA-mediated G(i) activation: but had no effect on cell rounding. Membrane binding studies indicated that vzg-1 overe xpression increased specific LPA binding. These analyses identify the vzg-1 gene product as a receptor for LPA, suggesting the operation of LPA signaling mechanisms in cortical neurogenesis. Vzg-1 therefore pro vides a link between extracellular LPA and the activation of LPA-media ted signaling pathways through a single receptor and will allow new in vestigations into LPA signaling both in neural and nonneural systems.