Bhattacharya Indrashis, Basu Sayon, Sarda Kanchan, Gautam Mukkesh, Nagarajan Perumal, Pradhan Bhola Shankar, Sarkar Hironmoy, Devi Yendrembam Sangeeta, Majumdar Subeer S
Cellular Endocrinology Laboratory (I.B., S.B., K.S., M.G., B.S.P., H.S., Y.S.D., S.S.M.) and Primate Research Centre (P.N., S.S.M.), National Institute of Immunology, New Delhi, India 110067.
Endocrinology. 2015 Mar;156(3):1143-55. doi: 10.1210/en.2014-1746. Epub 2014 Dec 30.
FSH acts via testicular Sertoli cells (Sc) bearing FSH receptor (FSH-R) for regulating male fertility. Despite an adult-like FSH milieu in infant boys and monkeys, spermatogenesis is not initiated until the onset of puberty. We used infant and pubertal monkey Sc to reveal the molecular basis underlying developmental differences of FSH-R signaling in them. Unlike pubertal Sc, increasing doses of FSH failed to augment cAMP production by infant Sc. The expression of Gαs subunit and Ric8b, which collectively activate adenylyl cyclase (AC) for augmenting cAMP production and gene transcription, were significantly low in infant Sc. However, forskolin, which acts directly on AC bypassing FSH-R, augmented cAMP production and gene transcription uniformly in both infant and pubertal Sc. FSH-induced Gαs mRNA expression was higher in pubertal Sc. However, Gαi-2 expression was down-regulated by FSH in pubertal Sc, unlike infant Sc. FSH failed, but forskolin or 8-Bromoadenosine 3',5'-cyclic monophosphate treatment to infant Sc significantly augmented the expression of transferrin, androgen binding protein, inhibin-β-B, stem cell factor, and glial-derived neurotropic factor, which are usually up-regulated by FSH in pubertal Sc during spermatogenic onset. This suggested that lack of FSH mediated down-regulation of Gαi-2 expression and limited expression of Gαs subunit as well as Ric8b may underlie limited FSH responsiveness of Sc during infancy. This study also divulged that intracellular signaling events downstream of FSH-R are in place and can be activated exogenously in infant Sc. Additionally, this information may help in the proper diagnosis and treatment of infertile individuals having abnormal G protein-coupled FSH-R.
促卵泡激素（FSH）通过睾丸中携带促卵泡激素受体（FSH-R）的支持细胞（Sc）发挥作用，以调节男性生育能力。尽管男婴和猴子体内的FSH环境与成年时相似，但精子发生直到青春期开始才启动。我们利用幼年和青春期猴子的支持细胞来揭示它们FSH-R信号发育差异的分子基础。与青春期支持细胞不同，增加FSH剂量并不能增强幼年支持细胞产生环磷酸腺苷（cAMP）的能力。在幼年支持细胞中，共同激活腺苷酸环化酶（AC）以增加cAMP产生和基因转录的Gαs亚基和Ric8b的表达显著较低。然而，直接作用于AC而绕过FSH-R的福斯可林，在幼年和青春期支持细胞中均能均匀地增加cAMP产生和基因转录。FSH诱导的Gαs mRNA表达在青春期支持细胞中较高。然而，与幼年支持细胞不同，FSH在青春期支持细胞中下调了Gαi-2的表达。FSH对幼年支持细胞无效，但福斯可林或3',5'-环磷酸腺苷（8-溴腺苷）处理幼年支持细胞可显著增加转铁蛋白、雄激素结合蛋白、抑制素-β-B蛋白、干细胞因子和胶质细胞源性神经营养因子的表达，这些蛋白在青春期支持细胞精子发生开始时通常由FSH上调。这表明，幼年期间支持细胞对FSH反应有限的原因可能是缺乏FSH介导的Gαi-2表达下调以及Gαs亚基和Ric8b的表达受限。这项研究还揭示，FSH-R下游的细胞内信号事件已经存在，并且可以在幼年支持细胞中外源性激活。此外，这些信息可能有助于对具有异常G蛋白偶联FSH-R的不育个体进行正确诊断和治疗。
