Kumar T R, Low M J, Matzuk M M
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Endocrinology. 1998 Jul;139(7):3289-95. doi: 10.1210/endo.139.7.6111.
FSH is an alpha:beta heterodimeric pituitary glycoprotein that shares a common alpha-subunit with LH and TSH. To study the role of FSH in mammalian reproduction, we have previously generated an FSH-deficient mouse model using embryonic stem (ES) cell technology by introducing a null mutation in the unique FSHbeta gene. Male mice deficient in FSH are fertile despite their small testes and reduced sperm number and motility. In contrast, FSH-deficient female mice are infertile due to a block in folliculogenesis at the preantral stage. In this set of experiments, we have rescued the mutant phenotypes of FSHbeta-deficient mice by two genetic strategies. In the type I rescue mice, we introduced into the FSHbeta-deficient background a 10-kb human FSHbeta transgene that is selectively expressed in pituitary gonadotropes. The presence of this transgene [and thus the interspecies hybrid (i.e. mouse alpha:human FSHbeta hormone)] in the background of mouse FSHbeta deficiency completely restored the testis size, sperm number, and motility defects to levels comparable to those seen in control male mice. All of the mouse FSHbeta-deficient female mice carrying this human FSHbeta transgene resumed normal folliculogenesis, were fertile and delivered normal size litters. In the type II rescue mice, human FSH (human alpha:human FSHbeta) was ectopically produced from multiple tissues in the mutant background using a mouse metallothionein-I promoter. Whereas ectopic production of human FSH completely rescued the mouse FSHbeta-deficient male mice, only 3 out of 10 mouse FSHbeta-deficient females bearing these human FSH transgenes were fertile and carried their pregnancies to term and parturition. We conclude that the resultant phenotypes due to a genetic deficiency of mouse FSHbeta can be corrected by appropriate expression of human FSH transgenes and that human FSHbeta gene regulation and function in the mouse pituitary are indistinguishable from the endogenous mouse FSHbeta gene.
促卵泡激素（FSH）是一种α:β异源二聚体垂体糖蛋白，与促黄体生成素（LH）和促甲状腺激素（TSH）共享一个共同的α亚基。为了研究FSH在哺乳动物生殖中的作用，我们之前利用胚胎干细胞（ES）技术，通过在独特的FSHβ基因中引入无效突变，构建了一个FSH缺陷小鼠模型。缺乏FSH的雄性小鼠尽管睾丸较小、精子数量减少且活力降低，但仍具有生育能力。相比之下，缺乏FSH的雌性小鼠由于在窦前阶段卵泡发生受阻而不育。在这组实验中，我们通过两种遗传策略挽救了FSHβ缺陷小鼠的突变表型。在I型挽救小鼠中，我们将一个10 kb的人类FSHβ转基因导入FSHβ缺陷背景中，该转基因在垂体促性腺激素细胞中选择性表达。在小鼠FSHβ缺陷背景中存在这个转基因[以及由此产生的种间杂种（即小鼠α:人类FSHβ激素）]，完全将睾丸大小、精子数量和活力缺陷恢复到与对照雄性小鼠相当的水平。所有携带这个人FSHβ转基因的小鼠FSHβ缺陷雌性小鼠都恢复了正常卵泡发生，并具有生育能力，产下了正常大小的窝仔。在II型挽救小鼠中，使用小鼠金属硫蛋白-I启动子在突变背景下从多个组织异位产生人类FSH（人类α:人类FSHβ）。虽然人类FSH的异位产生完全挽救了小鼠FSHβ缺陷雄性小鼠，但在10只携带这些人类FSH转基因的小鼠FSHβ缺陷雌性小鼠中，只有3只具有生育能力，并将妊娠维持到足月并分娩。我们得出结论，小鼠FSHβ基因缺陷导致的表型可以通过人类FSH转基因的适当表达得到纠正，并且人类FSHβ基因在小鼠垂体中的调控和功能与内源性小鼠FSHβ基因没有区别。
