Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
Biol Reprod. 2012 Jan 30;86(1):1-6. doi: 10.1095/biolreprod.111.094375. Print 2012 Jan.
Bidirectional signaling between oocytes and granulosa cells is required for normal folliculogenesis. Oocyte-secreted members of the transforming growth factor beta (TGFB) family, growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) are well-known mediators of granulosa cell function. Deletion in granulosa cells of Smad4, the common SMAD mediating all canonical TGFB-related protein signals, results in infertility. Reciprocal signaling by granulosa cell-expressed TGFB family ligands, such as activin, to the oocyte during follicle development has been proposed but not tested in vivo using conditional knockout mice. Therefore, we generated two oocyte-specific conditional knockout models for the common SMAD, Smad4, using cre recombinase expression from either the zona pellucida 3 (Zp3) or Gdf9 promoter. Cre expression from the Gdf9 promoter occurs at a slightly earlier time point in follicle development than from Zp3. Deletion of Smad4 using Zp3cre had no effect on fertility, while deletion of Smad4 with Gdf9icre resulted in a slight, but significant, reduction in litter size. These mouse models suggest a novel, although minor, role for Smad4 in the oocyte restricted to the primordial follicle stage.
卵母细胞和颗粒细胞之间的双向信号对于正常的卵泡发生是必需的。卵母细胞分泌的转化生长因子β（TGFB）家族成员，生长分化因子 9（GDF9）和骨形态发生蛋白 15（BMP15）是颗粒细胞功能的众所周知的介质。颗粒细胞中 Smad4 的缺失，即所有经典 TGFB 相关蛋白信号的共同 SMAD，导致不育。在卵泡发育过程中，颗粒细胞表达的 TGFB 家族配体（如激活素）向卵母细胞的相互信号传递已经被提出，但尚未在体内使用条件性敲除小鼠进行测试。因此，我们使用来自透明带 3（Zp3）或 Gdf9 启动子的 cre 重组酶表达，生成了两个卵母细胞特异性的 Smad4 条件性敲除模型，用于常见的 SMAD。Gdf9 启动子中的 cre 表达在卵泡发育中比 Zp3 更早发生。使用 Zp3cre 删除 Smad4 对生育能力没有影响，而使用 Gdf9icre 删除 Smad4 则导致产仔数略有但显著减少。这些小鼠模型表明 Smad4 在卵母细胞中的作用是新颖的，尽管作用较小，但仅限于原始卵泡阶段。
