PGE2 inhibits spermatogonia differentiation in zebrafish: interaction with Fsh and an androgen.

Changes in zebrafish testicular gene expression induced by follicle-stimulating hormone (Fsh) or anti-Mullerian hormone (Amh) suggested that Amh inhibition and Fsh stimulation of spermatogenesis involved up and downregulation, respectively, of prostaglandin (PG) signaling. We found that Sertoli cells contacting type A undifferentiated (A(und)) and differentiating (A(diff)) spermatogonia expressed a key enzyme of PG production (Ptgs2); previous work showed that Sertoli cells contacting A(diff)( )and B spermatogonia and spermatocytes showed ptges3b expression, an enzyme catalyzing PGE(2) production. In primary testis tissue cultures, PGE(2), but not PGD(2) or PGF(2 alpha), reduced the mitotic activity of A(diff) and their development into B spermatogonia. Vice versa, inhibiting PG production increased the mitotic activity of A(diff) and B spermatogonia. Studies with pharmacological PG receptor antagonists suggest that an Ep4 receptor mediates the inhibitory effects on the development of spermatogonia, and cell-sorting experiments indicated this receptor is expressed mainly by testicular somatic cells. Combined inhibition of PG and steroid production moreover reduced the mitotic activity of A(und) spermatogonia and led to their partial depletion, suggesting that androgens (and/or other testicular steroids), supported by PGE(2), otherwise prevent depletion of A(und). Androgens also decreased testicular PGE(2) production, increased the transcript levels of the enzyme-catabolizing PGs and decreased PGE(2) receptor ptger4b transcript levels. Also Fsh potentially reduced, independent of androgens, PGE(2) production by decreasing ptges3b transcript levels. Taken together, our results indicate that PGE(2), via Ep4 receptors, favors self-renewal in conjunction with androgens and, independent of Fsh and androgens, inhibits differentiating divisions of spermatogonia.