Tarrant A M, Greytak S R, Callard G V, Hahn M E
Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, USA.
J Mol Endocrinol. 2006 Aug;37(1):105-20. doi: 10.1677/jme.1.01976.
The estrogen receptor-related receptors (ERRs) are a group of nuclear receptors that were originally identified on the basis of sequence similarity to the estrogen receptors. The three mammalian ERR genes have been implicated in diverse physiological processes ranging from placental development to maintenance of bone density, but the diversity, function, and regulation of ERRs in non-mammalian species are not well understood. In this study, we report the cloning of four ERR cDNAs from the Atlantic killifish, Fundulus heteroclitus, along with adult tissue expression and estrogen responsiveness. Phylogenetic analysis indicates that F. heteroclitus (Fh)ERRalpha is an ortholog of the single ERRalpha identified in mammals, pufferfish, and zebrafish. FhERRbetaa and FhERRbetab are co-orthologs of the mammalian ERRbeta. Phylogenetic placement of the fourth killifish ERR gene, tentatively identified as FhERRgammab, is less clear. The four ERRs showed distinct, partially overlapping mRNA expression patterns in adult tissues. FhERRalpha was broadly expressed. FhERRbetaa was expressed at apparently low levels in eye, brain, and ovary. FhERRbetab was expressed more broadly in liver, gonad, eye, brain, and kidney. FhERRgammab was expressed in multiple tissues including gill, heart, kidney, and eye. Distinct expression patterns of FhERRbetaa and FhERRbetab are consistent with subfunctionalization of the ERRbeta paralogs. Induction of ERRalpha mRNA by exogenous estrogen exposure has been reported in some mammalian tissues. In adult male killifish, ERR expression did not significantly change following estradiol injection, but showed a trend toward a slight induction (three- to five-fold) of ERRalpha expression in heart. In a second, more targeted experiment, expression of ERRalpha in adult female killifish was downregulated 2.5-fold in the heart following estradiol injection. In summary, our results indicate that killifish contain additional ERR genes relative to mammals, including ERRbeta paralogs. In addition, regulation of ERRalpha expression in killifish apparently differs from regulation in mammals. Together, these features may facilitate determination of both conserved and specialized ERR gene functions.
雌激素受体相关受体（ERRs）是一类核受体，最初是根据与雌激素受体的序列相似性而被鉴定出来的。三种哺乳动物ERR基因已被证明参与了从胎盘发育到维持骨密度等多种生理过程，但非哺乳动物物种中ERRs的多样性、功能和调控尚不清楚。在本研究中，我们报告了从大西洋鳉鱼（Fundulus heteroclitus）中克隆出四个ERR cDNA，以及它们在成体组织中的表达和雌激素反应性。系统发育分析表明，F. heteroclitus（Fh）ERRalpha是在哺乳动物、河豚和斑马鱼中鉴定出的单一ERRalpha的直系同源物。FhERRbetaa和FhERRbetab是哺乳动物ERRbeta的共直系同源物。暂定为FhERRgammab的第四个鳉鱼ERR基因的系统发育位置尚不清楚。这四种ERRs在成体组织中表现出不同的、部分重叠的mRNA表达模式。FhERRalpha广泛表达。FhERRbetaa在眼睛、大脑和卵巢中表达水平明显较低。FhERRbetab在肝脏、性腺、眼睛、大脑和肾脏中表达更广泛。FhERRgammab在包括鳃、心脏、肾脏和眼睛在内的多种组织中表达。FhERRbetaa和FhERRbetab不同的表达模式与ERRbeta旁系同源物的亚功能化一致。在一些哺乳动物组织中，已报道外源性雌激素暴露可诱导ERRalpha mRNA表达。在成年雄性鳉鱼中，注射雌二醇后ERR表达没有显著变化，但心脏中ERRalpha表达有轻微诱导（三到五倍）的趋势。在第二个更有针对性的实验中，成年雌性鳉鱼注射雌二醇后，心脏中ERRalpha的表达下调了2.5倍。总之，我们的结果表明，相对于哺乳动物，鳉鱼含有额外的ERR基因，包括ERRbeta旁系同源物。此外，鳉鱼中ERRalpha表达的调控明显不同于哺乳动物中的调控。这些特征共同可能有助于确定ERR基因保守和特殊的功能。
