Gaemers I C, Sonneveld E, van Pelt A M, Schrans B H, Themmen A P, van der Saag P T, de Rooij D G
Department of Cell Biology, Medical School, Utrecht University, The Netherlands.
Endocrinology. 1998 Oct;139(10):4269-76. doi: 10.1210/endo.139.10.6272.
Retinoid X receptors (RXRs) are key regulators in retinoid signaling. Knowledge about the effects of 9-cis-retinoic acid (9-cis-RA), the natural ligand for the RXRs, may also provide insight in the functions of RXRs. In this study, the effect of 9-cis-RA on spermatogenesis in vitamin A-deficient (VAD) mice was examined. Administration of 9-cis-RA stimulated the differentiation and subsequent proliferation of the growth-arrested A spermatogonia in the testis of VAD mice. However, compared with all-trans-retinoic acid (ATRA), relatively higher doses of 9-cis-RA were necessary. This could not simply be due to a lower or delayed activity of 9-cis-RA, as simultaneous administration of ATRA and 9-cis-RA did not cause a synergistic effect. Instead, the presence of 9-cis-RA diminished the effect of ATRA by approximately one third. Studies of in vivo transport and metabolism showed that ATRA and 9-cis-RA, after administration to VAD mice, penetrated the testis equally well. However, 9-cis-RA was metabolized much faster than ATRA, and other metabolites were formed. This may account for the above-described differential effects of ATRA and 9-cis-RA on spermatogenesis. Similar to ATRA, 9-cis-RA transiently induced the messenger RNA expression of the nuclear RA receptor RAR beta, suggesting a role for this receptor in the effects of retinoids on the differentiation and proliferation of A spermatogonia. In contrast, the messenger RNA expression of the nuclear retinoid receptors RXR alpha, -beta, and -gamma was not changed significantly by administration of their ligand, 9-cis-RA. Hence, 9-cis-RA does not seem to exert its effect on spermatogenesis through altered expression of the RXRs.
维甲酸X受体（RXRs）是维甲酸信号通路中的关键调节因子。了解RXRs的天然配体9-顺式维甲酸（9-cis-RA）的作用，也可能有助于深入了解RXRs的功能。在本研究中，检测了9-顺式维甲酸对维生素A缺乏（VAD）小鼠精子发生的影响。给予9-顺式维甲酸可刺激VAD小鼠睾丸中生长停滞的A型精原细胞的分化及随后的增殖。然而，与全反式维甲酸（ATRA）相比，需要相对更高剂量的9-顺式维甲酸。这不能简单地归因于9-顺式维甲酸活性较低或作用延迟，因为同时给予ATRA和9-顺式维甲酸并未产生协同效应。相反，9-顺式维甲酸的存在使ATRA的作用降低了约三分之一。体内转运和代谢研究表明，给予VAD小鼠后，ATRA和9-顺式维甲酸穿透睾丸的能力相当。然而，9-顺式维甲酸的代谢速度比ATRA快得多，并且形成了其他代谢产物。这可能解释了上述ATRA和9-顺式维甲酸对精子发生的不同作用。与ATRA相似，9-顺式维甲酸可短暂诱导核维甲酸受体RARβ的信使RNA表达，表明该受体在维甲酸对A型精原细胞分化和增殖的作用中发挥作用。相比之下，给予其配体9-顺式维甲酸后，核维甲酸受体RXRα、-β和-γ的信使RNA表达没有明显变化。因此，9-顺式维甲酸似乎不是通过改变RXRs的表达来发挥其对精子发生的作用。
