Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, NE, USA.
Biol Reprod. 2022 Sep 12;107(3):800-812. doi: 10.1093/biolre/ioac111.
Estradiol-17β has been shown to promote primordial follicle formation and to involve bone morphogenetic protein 2 (BMP2) as a downstream effector to promote primordial follicle in hamsters. However, the molecular mechanism whereby these factors regulate ovarian somatic cells to pre-granulosa cells transition leading to primordial follicle formation remains unclear. The objective of this study was to determine whether BMP2 and/or estradiol-17β would regulate the expression of specific ovarian transcriptome during pre-granulosa cells transition and primordial follicle formation in the mouse ovary. BMP2 mRNA level increased during the period of primordial follicle formation with the concurrent presence of BMP2 protein in ovarian somatic cells. Estradiol-17β but not BMP2 exposure led to increased expression of ovarian BMP2 messenger RNA (mRNA), and the effect of estradiol-17β could not be suppressed by 4-[6-[4-(1-Piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline dihydrochloride (LDN) 193189. BMP2 or estradiol-17β stimulated primordial follicle formation without inducing apoptosis. Ribonucleic acid-sequence analysis (RNA-seq) of ovaries exposed to exogenous BMP2 or estradiol-17β revealed differential expression of several thousand genes. Most of the differentially expressed genes, which were common between BMP2 or estradiol-17β treatment demonstrated concordant changes, suggesting that estradiol-17β and BMP2 affected the same set of genes during primordial follicle formation. Further, we have identified that estradiol-17β, in cooperation with BMP2, could affect the expression of three major transcription factors, GATA binding protein 2, GATA binding protein 4 and Early growth response 2, and one serine protease, hepsin, in pre-granulosa cells during primordial follicle formation. Taken together, results of this study suggest that estradiol-17β and BMP2 may regulate ovarian gene expression that promote somatic cells to pre-granulosa cells transition and primordial follicle formation in the mouse ovary.
雌二醇-17β 已被证明可促进原始卵泡的形成，并涉及骨形态发生蛋白 2（BMP2）作为下游效应物，以促进仓鼠的原始卵泡。然而，这些因素调节卵巢体细胞向原始卵泡形成的颗粒细胞前体细胞的分子机制尚不清楚。本研究的目的是确定 BMP2 和/或雌二醇-17β 是否会在小鼠卵巢中调节原始卵泡形成过程中颗粒细胞前体细胞过渡和原始卵泡形成期间特定的卵巢转录组的表达。BMP2mRNA 水平在原始卵泡形成期间增加，同时在卵巢体细胞中存在 BMP2 蛋白。雌二醇-17β 但不是 BMP2 暴露导致卵巢 BMP2 信使 RNA（mRNA）表达增加，并且雌二醇-17β 的作用不能被 4-[6-[4-(1-哌嗪基)苯基]吡唑并[1,5-a]嘧啶-3-基]喹啉二盐酸盐（LDN）193189 抑制。BMP2 或雌二醇-17β 刺激原始卵泡形成而不诱导细胞凋亡。外源性 BMP2 或雌二醇-17β 处理的卵巢的核糖核酸序列分析（RNA-seq）显示数千个基因的差异表达。大多数在 BMP2 或雌二醇-17β 处理中共同表达的差异表达基因表现出一致的变化，这表明雌二醇-17β 和 BMP2 在原始卵泡形成过程中影响同一组基因。此外，我们已经确定，雌二醇-17β 与 BMP2 合作，可以影响三个主要转录因子 GATA 结合蛋白 2、GATA 结合蛋白 4 和早期生长反应 2 以及一种丝氨酸蛋白酶 hepsin 在原始卵泡形成过程中颗粒细胞前体细胞中的表达。总之，本研究结果表明，雌二醇-17β 和 BMP2 可能调节卵巢基因表达，促进体细胞向原始卵泡形成的颗粒细胞前体细胞过渡。
