Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex.

Abstract

Abstract. Neocortical neuroblast cell lines were used to clone G-protein-coupled receptor (GPCR) genes to study signaling mechanisms regulating cortical neurogenesis. One putative GPCR gene displayed an in situ expression pattern enriched in cortical neurogenic regions and was therefore named ventricular zone gene-! (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 function, vzg-1 was overexpressed in a cell line from which it was cloned, inducing serum-dependent "cell rounding." Lysophosphatidic acid (LPA), a bioactive lipid present in high concentrations in serum, reproduced the effect seen with serum alone. Morphological responses to other related phospholipids or to thrombin, another agent that induces cell rounding through a GPCR, were not observed in vzg-1 overexpressing cells. Vzg-1 overexpression decreased the EC50 of both cell rounding and Gi activation in response to LPA. Pertussis toxin treatment inhibited vzg-l-dependent LPA-mediated Gi activation, but had no effect on cell rounding. Membrane binding studies indicated that vzg-1 overexpression 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 provides a link between extracellular LPA and the activation of LPAmediated signaling pathways through a single receptor and will allow new investigations into LPA signaling both in neural and nonneural systems.CRITICAL event in the formation of the mammalian cerebral cortex is the ordered generation of its neurons from a discrete proliferative region overlying the cerebral ventricles, the ventricular zone (vz) t (6), (Fig. 1). In most mammalian species, neurogenesis occurs during fetal life when the vz can be delineated by histological stains, or by brief pulses of 5-Bromo-2'-deoxyuridine (BrdU) or [3H]thymidine, which identify neuroblasts undergoing S-phase (58,64,67). Cortical neuroblasts display a stereotyped change in their morphology that is linked to their proliferation. During S-phase of the cell cycle, vz neuroblasts appear bipolar, with the cell body at the super-

Expression patterns of the lysophospholipid receptor genes during mouse early development

“…5H). Expression of Lpa 1 in the cortical ventricular zone of the dorsal telencephalon from E12 onward has been reported (Hecht et al, 1996). Our data showed the expression of Lpa 1 in the future cerebral cortex has already begun at E11.5 and persists through E12.5 (Supp.…”

“…Lpa 1 was originally identified in neocortical neuroblast cell lines, and was found, in the mouse, to be enriched in the cortical ventricular zone of the dorsal telencephalon from E12 onward (Hecht et al, 1996). It was further determined that Lpa 1 expression is biphasic, and that during the second phase of its expression in the postnatal brain, Lpa 1 is expressed by differentiated oligodendrocytes, the predominant cells being produced in the white matter tracts at this stage (Weiner et al, 1998).…”

Nuclear migration during retinal development

“…For cortical progenitors in culture, exogenous lysophosphatidic acid (LPA) was found to promote nuclear movements and retraction of lamellipodia, resulting in a cell-rounding phenotype reminiscent of G2/M-phase cells of the ventricular zone (Fukushima et al, 2000). In vivo, the LPA receptor EDG2 (Endothelial Differentiation Gene 2) is highly enriched within the ventricular zone (Hecht et al, 1996). Bioassays of conditioned medium suggested that post-mitotic neurons are the source of secreted LPA.…”

Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3

“…[ [18][19][20]. Among these cDNAs, three kinds of orphan receptor cDNAs, Edg-1, Edg-3 and AGR16\H218 (Edg-5) have recently been identified as S1P receptors [21][22][23].…”