The TGF-β superfamily members and their antagonists comprise an indispensable system that controls mammalian ovarian development in a sophisticated manner. In contrast to a plethora of studies on the ovary-expressed TGF-β superfamily members, knowledge regarding their antagonists, including their expression profiles and antagonism preferences, is still lacking. Using quantitative PCR in rats and transcriptomic dataset comparisons in mice and humans, we set out to characterize the relative expression levels of most antagonists in the mammalian ovary. We found that Twsg1 and Nbl1 are the most abundant BMP antagonists expressed in the rodent and human ovaries, respectively. TWSG1 has been reported to have synergistic action with the chordin subfamily, including CHRD and CHRDL1, the genes of which also showed moderate expression in the mammalian ovary. Therefore, their ovarian expression profiles and antagonisms against the ovary-expressed TGF-β superfamily members were further characterized. Bioactivity tests indicated that TWSG1 alone can directly inhibit the signaling of BMP6 or BMP7. In addition, it can further enhance the antagonizing ability of CHRD towards BMP2, BMP4, BMP7 and GDF5, or CHRDL1's antagonism towards BMP2, BMP4, GDF5 and activin A. In combination with their distinct transcript profiles in ovarian compartments, our findings suggest that TWSG1 may work coordinately with CHRD within theca/interstitial shells and also with CHRDL1 in developing granulosa cells; these interactions would modulate the intraovarian functions of the TGF-β superfamily members, such as the control of progesterone production.

TGF-β 超家族成员及其拮抗剂构成了以复杂方式控制哺乳动物卵巢发育的不可或缺的系统。与对卵巢表达的 TGF-β 超家族成员的大量研究相比，仍然缺乏关于其拮抗剂的知识，包括它们的表达谱和拮抗偏好。使用大鼠的定量 PCR 和小鼠和人类的转录组数据集比较，我们开始描述哺乳动物卵巢中大多数拮抗剂的相对表达水平。我们发现Twsg1和Nbl1是分别在啮齿动物和人类卵巢中表达的最丰富的 BMP 拮抗剂。据报道，TWSG1 与脊索蛋白亚科具有协同作用，包括 CHRD 和 CHRDL1，其基因在哺乳动物卵巢中也表现出适度的表达。因此，进一步表征了它们的卵巢表达谱和对卵巢表达的 TGF-β 超家族成员的拮抗作用。生物活性测试表明单独的 TWSG1 可以直接抑制 BMP6 或 BMP7 的信号传导。此外，它还可以进一步增强 CHRD 对 BMP2、BMP4、BMP7 和 GDF5 的拮抗能力，或 CHRDL1 对 BMP2、BMP4、GDF5 和激活素 A 的拮抗作用。结合它们在卵巢区室中不同的转录谱，我们的研究结果表明，TWSG1 可能与囊/间质壳内的 CHRD 协同工作，也可能与发育中的颗粒细胞的 CHRDL1 协同工作；这些相互作用将调节 TGF-β 超家族成员的卵巢内功能，例如控制黄体酮的产生。