Department of Biochemistry, Monash University, Melbourne 3800, Australia.
Endocrinology. 2011 May;152(5):2076-89. doi: 10.1210/en.2010-1453. Epub 2011 Mar 8.
The establishment and maturation of the testicular Sertoli cell population underpins adult male fertility. These events are influenced by hormones and endocrine factors, including FSH, testosterone and activin. Activin A has developmentally regulated effects on Sertoli cells, enhancing proliferation of immature cells and later promoting postmitotic maturation. These differential responses correlate with altered mothers against decapentaplegic (SMAD)-2/3 signaling: immature cells signal via SMAD3, whereas postmitotic cells use both SMAD2 and SMAD3. This study examined the contribution of SMAD3 to postnatal mouse testis development. We show that SMAD3 production and subcellular localization are highly regulated and, through histological and molecular analyses, identify effects of altered Smad3 dosage on Sertoli and germ cell development. Smad3(+/-) and Smad3(-/-) mice had smaller testes at 7 d postpartum, but this was not sustained into adulthood. Juvenile and adult serum FSH levels were unaffected by genotype. Smad3-null mice displayed delayed Sertoli cell maturation and had reduced expression of androgen receptor (AR), androgen-regulated transcripts, and Smad2, whereas germ cell and Leydig cell development were essentially normal. This contrasted remarkably with advanced Sertoli and germ cell maturation and increased expression of AR and androgen-regulated transcripts in Smad3(+/-) mice. In addition, SMAD3 was down-regulated during testis development and testosterone up-regulated Smad2, but not Smad3, in the TM4 Sertoli cell line. Collectively these data reveal that appropriate SMAD3-mediated signaling drives normal Sertoli cell proliferation, androgen responsiveness, and maturation and influences the pace of the first wave of spermatogenesis, providing new clues to causes of altered pubertal development in boys.
睾丸支持细胞群体的建立和成熟是成年男性生育能力的基础。这些事件受到激素和内分泌因素的影响，包括 FSH、睾酮和激活素。激活素 A 对支持细胞具有发育调节作用，增强未成熟细胞的增殖，随后促进有丝分裂后成熟。这些不同的反应与改变的母亲对抗 decapentaplegic (SMAD)-2/3 信号相关：未成熟细胞通过 SMAD3 信号转导，而有丝分裂后细胞同时使用 SMAD2 和 SMAD3。本研究检查了 SMAD3 对出生后小鼠睾丸发育的贡献。我们表明，SMAD3 的产生和亚细胞定位受到高度调节，并通过组织学和分子分析，确定了改变 Smad3 剂量对支持细胞和生殖细胞发育的影响。Smad3(+/-)和 Smad3(-/-)小鼠在产后 7 天睾丸较小，但这种情况不会持续到成年期。幼年和成年血清 FSH 水平不受基因型影响。Smad3 缺失小鼠显示支持细胞成熟延迟，雄激素受体 (AR)、雄激素调节转录物和 Smad2 的表达减少，而生殖细胞和莱迪希细胞发育基本正常。这与 Smad3(+/-)小鼠中支持细胞和生殖细胞成熟提前以及 AR 和雄激素调节转录物表达增加形成鲜明对比。此外，SMAD3 在睾丸发育过程中下调，而 TM4 支持细胞系中的睾酮上调 Smad2，但不上调 Smad3。总的来说，这些数据表明适当的 SMAD3 介导的信号转导驱动正常的支持细胞增殖、雄激素反应性和成熟，并影响第一次精子发生波的速度，为男孩青春期发育改变的原因提供了新的线索。
