Brooks Kelsey, Burns Gregory, Spencer Thomas E
Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, Washington.
Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, Washington
Biol Reprod. 2015 Aug;93(2):38. doi: 10.1095/biolreprod.115.130757. Epub 2015 Jun 17.
In sheep, the elongating conceptus synthesizes and secretes interferon tau (IFNT) as well as prostaglandins (PGs) and cortisol. The enzymes, hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) and HSD11B2 interconvert cortisone and cortisol. In sheep, HSD11B1 is expressed and active in the conceptus trophectoderm as well as in the endometrial luminal epithelia; in contrast, HSD11B2 expression is most abundant in conceptus trophectoderm. Cortisol is a biologically active glucocorticoid and ligand for the glucocorticoid receptor (NR3C1 or GR) and mineralocorticoid receptor (NR3C2 or MR). Expression of MR is not detectable in either the ovine endometrium or conceptus during early pregnancy. In tissues that do not express MR, HSD11B2 protects cells from the growth-inhibiting and/or proapoptotic effects of cortisol, particularly during embryonic development. In study one, an in utero loss-of-function analysis of HSD11B1 and HSD11B2 was conducted in the conceptus trophectoderm using morpholino antisense oligonucleotides (MAOs) that inhibit mRNA translation. Elongating, filamentous conceptuses were recovered on Day 14 from ewes infused with control morpholino or HSD11B2 MAO. In contrast, HSD11B1 MAO resulted in severely growth-retarded conceptuses or conceptus fragments with apoptotic trophectoderm. In study two, clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing was used to determine the role of GR in conceptus elongation and development. Elongating, filamentous-type conceptuses (12-14 cm in length) were recovered from ewes gestating control embryos (n = 7/7) and gestating GR-edited embryos (n = 6/7). These results support the idea that the effects of HSD11B1-derived cortisol on conceptus elongation are indirectly mediated by the endometrium and are not directly mediated through GR in the trophectoderm.
在绵羊中，正在伸长的孕体合成并分泌干扰素τ（IFNT）以及前列腺素（PGs）和皮质醇。羟类固醇（11-β）脱氢酶1（HSD11B1）和HSD11B2这两种酶可相互转化可的松和皮质醇。在绵羊中，HSD11B1在孕体滋养外胚层以及子宫内膜腔上皮中表达且具有活性；相比之下，HSD11B2的表达在孕体滋养外胚层中最为丰富。皮质醇是一种具有生物活性的糖皮质激素，是糖皮质激素受体（NR3C1或GR）和盐皮质激素受体（NR3C2或MR）的配体。在妊娠早期，绵羊子宫内膜或孕体中均未检测到MR的表达。在不表达MR的组织中，HSD11B2可保护细胞免受皮质醇的生长抑制和/或促凋亡作用，尤其是在胚胎发育期间。在研究一中，使用抑制mRNA翻译的吗啉代反义寡核苷酸（MAO），在孕体滋养外胚层中对HSD11B1和HSD11B2进行子宫内功能丧失分析。在第14天从注入对照吗啉代或HSD11B2 MAO的母羊中回收正在伸长的丝状孕体。相比之下，HSD11B1 MAO导致孕体严重生长迟缓或出现带有凋亡滋养外胚层的孕体片段。在研究二中，使用成簇规律间隔短回文重复序列（CRISPR）/Cas9基因组编辑来确定GR在孕体伸长和发育中的作用。从妊娠对照胚胎（n = 7/7）和妊娠GR编辑胚胎（n = 6/7）的母羊中回收正在伸长的丝状类型孕体（长度为12 - 14厘米）。这些结果支持以下观点：HSD11B1衍生的皮质醇对孕体伸长的影响是由子宫内膜间接介导的，而非通过滋养外胚层中的GR直接介导。
