Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. In recent years, identification of multiple cognate G protein-coupled receptors has provided a mechanistic framework for understanding how LPs play such diverse roles. Generation of LP receptor-null animals has allowed rigorous examination of receptor-mediated physiological functions in vivo and has identified new functions for LP receptor signaling. Efforts to develop LP receptor subtype-specific agonists/antagonists are in progress and raise expectations for a growing collection of chemical tools and potential therapeutic compounds. The rapidly expanding literature on the LP receptors is herein reviewed.

Every successful pregnancy requires proper embryo implantation. Low implantation rate is a major problem during infertility treatments using assisted reproductive technologies (ART) 1 . Here we report a new molecular influence on implantation through the lysophosphatidic acid (LPA) receptor LPA 3 2-4 . Targeted deletion of LPA 3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos, and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase-2 (COX-2) 5 , was downregulated in LPA 3 -deficient uteri during preimplantation. Down regulation of COX-2 led to reduced levels of prostaglandins that are critical for implantation 1 . Exogenous administration of the prostaglandins PGE 2 and cPGI into LPA 3 -deficient females rescued delayed implantation but did not rescue defects in embryo spacing. These data identify LPA 3 receptor-mediated signalling as a new influence on implantation and further indicate linkage between LPA signalling and prostaglandin biosynthesis.Multiple factors can adversely affect successful pregnancy. Two of these factors are failed synchronization between embryonic and endometrial development during implantation and occurrence of multiple gestations (especially monochorionic gestation), which can result in fetal demise 1,6-9 . These factors are particularly important for the clinical success and efficacy of ART. One molecular factor that has been previously implicated in female reproduction is the small, bioactive phospholipid LPA 10 . LPA has a range of influences that are mediated by at least four G protein-coupled receptors, LPA 1-4 2 . Deletion of LPA 1 and LPA 2 in mice revealed roles for these receptors in neural development, craniofacial formation, neuropathic pain, and altered cellular signalling, but without obvious effects on female reproduction 11-Correspondence and requests for materials should be addressed to J. Chun (e-mail:jchun@scripps.edu).. 6 These authors contributed equally to the work. Functional deletion of LPA 3 was achieved by replacing a fragment covering the untranslated region and the start codon in exon 2 with a neomycin-resistance gene in reverse orientation in R1 embryonic stem cells (supplementary Fig. S1). The LPA 3 -deficient mice were born with normal Mendelian frequency without sexual bias (supplementary Table S1), and appeared grossly normal (data not shown). However, LPA 3 -deficient females produced litter sizes of less than 50% compared to that from wild-type (WT) and LPA 3 heterozygote (Het) controls (supplementary Table S2), and showed a statistically significant prolongation of pregnancy (20.9±0.5 days, vs. 19.4±0.7 days in WT/Het controls, P<0.05). These phenotypes were independent of stud genotype, indicating defects in female reproduction. Supplementary InformationTowards determining whether LPA 3 deletion might directly affect the female...

Lysophosphatidic acid (LPA), a bioactive lipid produced by several cell types including postmitotic neurons and activated platelets, is thought to be involved in various biological processes, including brain development. Three cognate G protein-coupled receptors encoded by lpa 1 /lp A1 /Edg-2/Gpcr26, lpa 2 /lp A2 /Edg-4, and lpa 3 /lp A3 / Edg-7 mediate the cellular effects of LPA. We have previously shown that deletion of lpa 1 in mice results in craniofacial dysmorphism, semilethality due to defective suckling behavior, and generation of a small fraction of pups with frontal hematoma. To further investigate the role of these receptors and LPA signaling in the organism, we deleted lpa 2 in mice. Homozygous knockout (lpa 2 (؊/؊) ) mice were born at the expected frequency and displayed no obvious phenotypic abnormalities. fibroblasts. Thus, although LPA 2 is not essential for normal mouse development, it does act redundantly with LPA 1 to mediate most LPA responses in fibroblasts.