Male-specific expression of mouse sex-limited protein requires growth hormone, not testosterone.

Sex-limited protein (Slp), an isoform of mouse complement component C4, is expressed predominantly in liver and nearly exclusively in sexually mature males or testosterone-treated females. It is encoded by a gene (C4-Slp) whose hormonal dependence has been attributed to an androgen-responsive transcriptional enhancer introduced accidentally, alongside the C4-Slp promoter, in the guise of the 5' long terminal repeat of an ancient retrovirus. We demonstrate that the pronounced rise of C4-Slp mRNA promoted by androgens in the liver is due to nuclear factors acting at a transcriptional stage. Curiously, hypophysectomized animals of either sex fail to express the gene and are refractory to testosterone. However, gene expression at male levels is restored even more promptly by injections of growth hormone alone. Additionally, animals carrying an ubiquitously expressed human growth hormone transgene lack C4-Slp mRNA and are insensitive to testosterone treatment. That growth hormone is sufficient to induce expression in a manner independent of androgen-receptor activity is shown by the hormonal treatment of Tfm mice. These androgen receptor-defective animals lack C4-Slp mRNA, which however can be fully induced by growth hormone injections. We conclude that the sexual dimorphism of C4-Slp expression employs liver nuclear mediators distinct from those directly instructed by androgens and is brought about by the intermittent rise of growth hormone, dictated by testosterone.