No abstract

Pheromones play vital roles for survival and reproduction in various organisms. In many fishes, prostaglandin F2α acts not only as a female reproductive hormone, facilitating ovulation and spawning, but also as a sex pheromone inducing male reproductive behaviors. Here, we unravel the molecular and neural circuit mechanisms underlying the pheromonal action of prostaglandin F2α in zebrafish. Prostaglandin F2α specifically activates two olfactory receptors with different sensitivities and expression in distinct populations of ciliated olfactory sensory neurons. Pheromone information is then transmitted to two ventromedial glomeruli in the olfactory bulb and further to four regions in higher olfactory centers. Mutant male zebrafish deficient in the high-affinity receptor exhibit loss of attractive response to prostaglandin F2α and impairment of courtship behaviors toward female fish. These findings demonstrate the functional significance and activation of selective neural circuitry for the sex pheromone prostaglandin F2α and its cognate olfactory receptor in fish reproductive behavior.

Prostaglandins (PGs) are the major lipid mediators in animals and which are biosynthesized from arachidonic acid by the cyclooxygenases (COX-1 or COX-2) as the rate-limiting enzymes. Prostaglandin E2 (PGE2), which is the most abundantly detected PG in various tissues, exerts versatile physiological and pathological actions via four receptor subtypes (EP1–4). Non-steroidal anti-inflammatory drugs, such as aspirin and indomethacin, exert potent anti-inflammatory actions by the inhibition of COX activity and the resulting suppression of PG production. Therefore, PGE2 has been shown to exacerbate several inflammatory responses and immune diseases. Recently, studies using mice deficient in each PG receptor subtype have clarified the detailed mechanisms underlying PGE2-associated inflammation and autoimmune diseases involving each EP receptor. Here, we review the recent advances in our understanding of the roles of PGE2 receptors in the progression of acute and chronic inflammation and autoimmune diseases. PGE2 induces acute inflammation through mast cell activation via the EP3 receptor. PGE2 also induces chronic inflammation and various autoimmune diseases through T helper 1 (Th1)-cell differentiation, Th17-cell proliferation and IL-22 production from Th22 cells via the EP2 and EP4 receptors. The possibility of EP receptor-targeted drug development for the treatment of immune diseases is also discussed.

No abstract

No abstract

Lymphatic endothelial cells arise from the venous endothelial cells in embryonic lymphatic development. However, the molecular mechanisms remain to be elucidated. We here report that prostaglandin (PG) E 2 plays essential roles in the embryonic lymphatic development through the EP3 receptor, one of the PGE 2 receptors. Knockdown of the EP3 receptor or inhibition of cyclooxygenases (COX; rate-limiting enzymes for PG synthesis) impaired lymphatic development by perturbing lymphatic specification during zebrafish development. These impairments by COX inhibition were recovered by treatment with sulprostone (EP1/3 agonist). Knockdown of the EP3 receptor further demonstrated its requirement in the expression of sex determining region Y-box 18 (sox18) and nuclear receptor subfamily 2, group F, member 2 (nr2f2), essential factors of the lymphatic specification. The EP3 receptor was expressed in the posterior cardinal vein (region of embryonic lymphatic development) and the adjacent intermediate cell mass (ICM) during the lymphatic specification. COX1 was expressed in the region more upstream of the posterior cardinal vein relative to the EP3 receptor, and the COX1-selective inhibitor impaired the lymphatic specification. On the other hand, two COX2 subtypes did not show distinct sites of expression around the region of expression of the EP3 receptor. Finally, we generated EP3-deficient zebrafish, which also showed defect in lymphatic specification and development. Thus, we demonstrated that COX1-derived PGE 2 -EP3 pathway is required for embryonic lymphatic development by upregulating the expression of key factors for the lymphatic specification.

A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3′ to 5′ exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed.

No abstract