Activin A Balances Sertoli and Germ Cell Proliferation in the Fetal Mouse Testis
Activin A Balances Sertoli and Germ Cell Proliferation in the Fetal Mouse Testis
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DOI：
10.1095/biolreprod.110.086231
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发表时间：
2011-02-01
影响因子：
3.6
通讯作者：
Loveland, Kate L.
中科院分区：
文献类型：
--
作者：
Mendis, Sirisha H. S.;Meachem, Sarah J.;Loveland, Kate L.
激活素影响细胞发育的许多方面，包括那些对于生殖健康至关重要的方面。这项研究检查了激活素 A 对小鼠胎儿睾丸发育的贡献，揭示了激活素对支持细胞和性母细胞作用的对比结果。性别确定后不久，从胚胎第 12.5 天 (E12.5) 到出生 (0 dpp)，睾丸中的激活素 A 亚基转录物 (Inhba) 水平升高，但卵巢中并未升高，紧随其后的是 Inha 转录物（编码抑制性抑制素 α 亚基）。激活素受体转录水平也发生变化，与 E13.5 和 E15.5 相比，Acvr1（编码 ALK2）和 Acvr2b (ActRIIB) 在 0 dpp 时分别显着升高和降低。与 E13.5 和 E15.5 相比，编码信号传导介质 Smad1、Smad3 和 Smad4 的转录本在 0 dpp 时较高，而 Smad2、Smad5 和 Smad7 较低。在几乎所有睾丸细胞核中检测到磷酸化 (P-) SMAD2/3 表明存在广泛的转化生长因子 β (TGFB) 和/或激活素配体信号传导活性。与野生型同窝小鼠相比，激活素 betaA 亚基敲除 (Inhba(-/-)) 小鼠出生时睾丸明显较小，这归因于支持细胞数量减少 50%，并且支持细胞增殖从 E13.5 开始减少。 Inhba(-/-) 睾丸的生殖母细胞数量是出生时正常数量的两倍，其中一些似乎绕过了静止状态。 Inhba(-/-) 细胞中广泛存在的 P-SMAD2/3 的持续存在表明其他 TGFB 超家族配体在胎儿睾丸中也有活性。与 Inhba 基因剂量相关的 Smad 和细胞周期调节因子转录水平的显着差异对应于支持细胞和生殖细胞数量的差异。在 Inhba(-/-) 睾丸中，先前在胎儿生殖母细胞中鉴定出的 Cdkn1a（编码 p21(cip1)）在 E13.5 时较低，而 Cdkn1b（在体细胞中编码 p(27kip1)）在出生时较低，细胞周期蛋白 D2 mRNA 和蛋白质在 E15.5 和 0 dpp 时较低。因此，激活素 A 剂量有助于建立成年男性生育能力最终所需的支持细胞和生殖细胞数量之间的平衡。
Activin affects many aspects of cellular development, including those essential for reproductive fitness. This study examined the contribution of activin A to murine fetal testicular development, revealing contrasting outcomes of activin actions on Sertoli cells and gonocytes. Shortly after sex determination, from Embryonic Day 12.5 (E12.5) through to birth (0 dpp), the activin A subunit transcript (Inhba) level rises in testis but not ovary, followed closely by the Inha transcript (encoding the inhibitory inhibin alpha subunit). Activin receptor transcript levels also change, with Acvr1 (encoding ALK2) and Acvr2b (ActRIIB) significantly higher and lower, respectively, at 0 dpp compared with E13.5 and E15.5. Transcripts encoding the signaling mediators Smad1, Smad3, and Smad4 were higher at 0 dpp compared with E13.5 and E15.5, whereas Smad2, Smad5, and Smad7 were lower. Detection of phosphorylated (P-) SMAD2/3 in nearly all testis cell nuclei indicated widespread transforming growth factor beta (TGFB) and/or activin ligand signaling activity. In contrast to wild-type littermates, activin betaA subunit knockout (Inhba(-/-)) mice have significantly smaller testes at birth, attributable to a 50% lower Sertoli cell number and decreased Sertoli cell proliferation from E13.5. Inhba(-/-) testes contained twice the normal gonocyte number at birth, with some appearing to bypass quiescence. Persistence of widespread P-SMAD2/3 in Inhba(-/-) cells indicates other TGFB superfamily ligands are active in fetal testes. Significant differences in Smad and cell cycle regulator transcript levels correlating to Inhba gene dosage correspond to differences in Sertoli and germ cell numbers. In Inhba(-/-) testes, Cdkn1a (encoding p21(cip1)), identified previously in fetal gonocytes, was lower at E13.5, whereas Cdkn1b (encoding p(27kip1) in somatic cells) was lower at birth, and cyclin D2 mRNA and protein were lower at E15.5 and 0 dpp. Thus, activin A dosage contributes to establishing the balance between Sertoli and germ cell number that is ultimately required for adult male fertility.