Ovarian follicle development requires Smad3.
Ovarian follicle development requires Smad3.
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DOI：
10.1210/me.2003-0414
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发表时间：
2004-09
影响因子：
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通讯作者：
D. Tomić;K. Miller;H. Kenny;T. Woodruff;P. Hoyer;J. Flaws
中科院分区：
文献类型：
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作者：
D. Tomić;K. Miller;H. Kenny;T. Woodruff;P. Hoyer;J. Flaws
Smad 3是TGF β信号通路的重要介质。有趣的是，与野生型（WT）小鼠相比，Smad 3缺陷型（Smad 3-/-）小鼠的生育能力降低。为了更好地理解Smad 3-/-动物生育力降低的分子机制，这项工作测试了Smad 3缺乏干扰卵泡发生的三个关键方面的假设：生长，闭锁和分化。通过比较Smad 3-/-和WT小鼠的卵泡大小、增殖细胞核抗原表达和细胞周期基因表达来评估生长。通过比较Smad 3-/-和WT小鼠中闭锁的发生率和涉及细胞死亡和细胞存活的bcl-2基因的表达来评估闭锁。通过比较Smad 3-/-和WT小鼠中FSH受体（FSHR）、雌激素受体（ER）α、ER β和β-受体结合蛋白α、β（A）和β（B）亚基的表达来评估分化。由于生长、闭锁和分化受激素调节，因此在Smad 3-/-和WT小鼠中比较了雌二醇、FSH和LH水平。此外，由于卵泡发生的改变可影响小鼠排卵的能力，因此在Smad 3-/-和WT动物中比较了响应促性腺激素处理的黄体和排卵卵的数量。结果表明，Smad 3缺陷减缓卵泡生长，其特征在于卵泡直径小，增殖细胞核抗原水平低，细胞周期基因（细胞周期蛋白依赖性激酶4和细胞周期蛋白D2）表达低。Smad 3缺乏也会导致闭锁卵泡、卵母细胞退化和bcl-2低表达。此外，Smad 3缺陷影响卵泡分化，如通过ER β表达降低、ER α表达增加和Eclubin α亚基表达降低所证明的。Smad 3缺乏导致雌二醇水平低和FSH水平高。最后，Smad 3-/-卵巢没有黄体，并且它们在用外源性促性腺激素诱导排卵后不排卵。总的来说，这些数据提供了第一个证据，表明Smad 3-/-小鼠的生育能力降低是由于卵泡发育受损，与控制细胞周期进程，细胞存活和细胞分化的基因表达改变有关。Smad 3-/-卵泡在高FSH水平、FSHR正常表达和细胞周期蛋白D2表达较低的情况下生长受损、闭锁增加和分化改变，这一发现表明小鼠卵巢中Smad 3和FSHR下游FSH信号传导之间可能存在相互作用。
Smad3 is an important mediator of the TGF beta signaling pathway. Interestingly, Smad3-deficient (Smad3-/-) mice have reduced fertility compared with wild-type (WT) mice. To better understand the molecular mechanisms underlying the reduced fertility in Smad3-/- animals, this work tested the hypothesis that Smad3 deficiency interferes with three critical aspects of folliculogenesis: growth, atresia, and differentiation. Growth was assessed by comparing the size of follicles, expression of proliferating cell nuclear antigen, and expression of cell cycle genes in Smad3-/- and WT mice. Atresia was assessed by comparing the incidence of atresia and expression of bcl-2 genes involved in cell death and cell survival in Smad3-/- and WT mice. Differentiation was assessed by comparing the expression of FSH receptor (FSHR), estrogen receptor (ER) alpha, ER beta, and inhibin alpha-, beta(A)-, and beta(B)-subunits in Smad3-/- and WT mice. Because growth, atresia, and differentiation are regulated by hormones, estradiol, FSH, and LH levels were compared in Smad3-/- and WT mice. Moreover, because alterations in folliculogenesis can affect the ability of mice to ovulate, the number of corpora lutea and ovulated eggs in response to gonadotropin treatments were compared in Smad3-/- and WT animals. The results indicate that Smad3 deficiency slows follicle growth, which is characterized by small follicle diameters, low levels of proliferating cell nuclear antigen, and low expression of cell cycle genes (cyclin-dependent kinase 4 and cyclin D2). Smad3 deficiency also causes atretic follicles, degenerated oocytes, and low expression of bcl-2. Furthermore, Smad3 deficiency affects follicular differentiation as evidenced by decreased expression of ER beta, increased expression of ER alpha, and decreased expression of inhibin alpha-subunits. Smad3 deficiency causes low estradiol and high FSH levels. Finally, Smad3-/- ovaries have no corpora lutea, and they do not ovulate after ovulatory induction with exogenous gonadotropins. Collectively, these data provide the first evidence that reduced fertility in Smad3-/- mice is due to impaired folliculogenesis, associated with altered expression of genes that control cell cycle progression, cell survival, and cell differentiation. The findings that Smad3-/- follicles have impaired growth, increased atresia, and altered differentiation in the presence of high FSH levels, normal expression of FSHR, and lower expression of cyclin D2, suggest a possible interaction between Smad3 and FSH signaling downstream of FSHR in the mouse ovary.