Transforming growth factor beta signaling and decidual development in mice

Transforming growth factor beta (TGFbeta ) signaling regulates multifaceted reproductive processes via its transmembrane receptor complex-associated machinery. It has been shown that the type 1 receptor of TGFbeta (TGFBR1) is indispensable for female reproductive tract development, pregnancy success, and fertility. However, the role of TGFbeta signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on the differentiation of endometrial stromal cells in pregnant mice, with a focus on the cellular and molecular properties of the decidua. An approach combining histological and immunohistochemical analyses, quantitative PCR, western blot, and RNA-sequencing was utilized. Our results show that decidual development is altered in TGFBR1 conditionally depleted uteri, substantiated by downregulation of genes associated with inflammatory response and uterine natural killer cell abundance, reduced presence of non-decidualized fibroblasts in the antimesometrial region, and impaired decidual cell differentiation. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally-deleted decidua. The abnormal cell differentiation is accompanied with increased cell proliferation and enhanced decidual ERK1/2 signaling upon decidual regression. In summary, this study has identified an important role of TGFBR1 in decidual cell differentiation by revealing that conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 is required for the development of an integral decidua, a transient but crucial structure that supports embryo development. RNA sequencing of E6.5 wild type (WT) and Tgfbr1 Pgr-Cre knockout mouse decidual转化生长因子β（Transforming growth factor beta，TGFβ）信号通路通过其跨膜受体复合物相关机制调控多方面的生殖过程。已有研究表明，转化生长因子βⅠ型受体（TGFBR1）对于女性生殖道发育、妊娠成功及生育能力不可或缺。然而，转化生长因子β信号通路在蜕膜发育及功能中的作用仍未得到充分阐明。本研究旨在明确子宫特异性敲除Tgfbr1对妊娠小鼠子宫内膜基质细胞分化的影响，并重点关注蜕膜的细胞与分子特性。本研究采用组织学分析、免疫组织化学分析、定量PCR、蛋白质免疫印迹（western blot）及RNA测序（RNA-sequencing）相结合的实验方法。研究结果显示，TGFBR1条件性敲除的子宫中蜕膜发育出现异常，具体表现为炎症反应相关基因下调、子宫自然杀伤细胞丰度降低、系膜对侧区非蜕膜化成纤维细胞数量减少，以及蜕膜细胞分化受损。值得注意的是，与对照组相比，TGFBR1条件性敲除所形成的蜕膜在系膜对侧区的外周区域含有更多α平滑肌肌动蛋白（alpha smooth muscle actin，ACTA2）阳性细胞。该发现得到了验证：Tgfbr1条件性敲除的蜕膜中部分平滑肌标志物基因的表达上调。这种异常的细胞分化伴随细胞增殖增强，且在蜕膜退化阶段，蜕膜ERK1/2信号通路活性升高。综上，本研究通过揭示子宫内TGFBR1条件性敲除可显著影响蜕膜的细胞与分子特性，明确了TGFBR1在蜕膜细胞分化中的重要作用。研究结果表明，TGFBR1对于完整蜕膜的形成所必需，而蜕膜是一种可支持胚胎发育的短暂但关键的结构。对E6.5野生型（wild type，WT）及Tgfbr1 Pgr-Cre敲除小鼠蜕膜的RNA测序