Lysophosphatidic Acid Receptor-Specific Functions in Uterine Receptivity and Spermatogenesis.

Abstract

Lysophosphatidic acid (LPA) is a small lipid signaling molecule abundant in serum. At least five LPA receptors, LPA1-5, have been identified. LPA receptors can couple with G12/13, Gq, Gi/o, or Gs to activate the downstream signaling cascades leading to LPA-induced cellular functions, such as cell proliferation, cell survival, cell differentiation, and cell morphological changes. Characterization of defined in vivo functions of LPA signaling in the reproductive system is being achieved through LPA receptor knockout mice. Available data reveal that receptor-mediated LPA signaling is critical for uterine receptivity and spermatogenesis. Among the five known LPA receptors, LPA1, LPA2, and LPA3, but not LPA4 or LPA5, are highly expressed in both pre-implantation uterus and in testis. Interestingly, deletion of LPA3, but not LPA1 or LPA2, results in delayed implantation. LPA3 is almost exclusively expressed in the luminal endometrial epithelium while the other LPA receptors have comparable expression levels in luminal endometrial epithelium, stroma, and myometrium. Additionally, only LPA3 is up-regulated by progesterone although all LPA receptors are down-regulated by estrogen. The differential expression pattern in uterus and up-regulation by progesterone may define LPA3 receptor-specificity in uterine receptivity. On the other hand, LPA1, LPA2, and LPA3 are all involved in spermatogenesis, reflected by degeneration of germ cells and reduced sperm counts in single receptor knock out testes, as well as by very dramatic phenotypes in LPA1(-/-)LPA2(-/-)LPA3(-/-) triple knockout testes. Deletion of LPA1, LPA2, and LPA3 results in increased germ cell apoptosis in the testis, which in turn leads to reduced germ cell proliferation. The consequence is deteriorated spermatogenesis and reduced sperm counts. These results indicate that LPA1, LPA2, and LPA3 are all involved in mediating LPA signaling as a male germ cell survival factor. The data demonstrate clearly that there is LPA receptor-specificity both in uterine receptivity and in spermatogenesis. (NIH R01 HD050685)