To probe genetic variation in the regulation of sexual dimorphism, we have characterized the mouse protein Slp, coded by the gene sex-limited protein (Slp). Slp expression in many strains is limited to males and is androgen-dependent. However, female expression is also observed in rare strains, due to nonlinked gene(s) termed regulator of sex-limitation (rsl). In As in other mammals, the tissue-specific levels of expression of many proteins differ between male and female mice, and the differences are frequently dependent upon the expression of gonadal hormones. A few of many examples of sexually dimorphic protein expression in mice are aromatase in brain, acidic epididymal glycoprotein and nerve growth factor in submandibular gland, 1113-hydroxysteroid dehydrogenase in kidney, steroid 16a-hydroxylase P45016a and steroid 15a-hydroxylase P45015a in liver, urinary proteins, and complement proteins C5, C6, and C7 in sera (1-7). In mammalian development, it is believed that the product of a single Y chromosome-borne gene (Sty in the mouse) is the switch that changes the gonad development from the default female pathway to the male pathway. In its simplest form, this one-switch model suggests that other differences between the sexes result directly from the subsequent sex-specific production of gonadal hormones (8, 9). However, not all sexual dimorphisms can be explained solely by this simple model. For The sex-limited protein (Slp), a serum glycoprotein, provides a dramatic example of sexual dimorphism in mice, and a potential model system for studying differential expression in males and females. Slp is the product of the gene Slp, locatedThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement' in accordance with 18 U.S.C. §1734 solely to indicate this fact.in the H-2 (11). The name Slp was derived from the original observation that the protein was found only in males of the investigated strains (12). Slp was found in several independent haplotypes (Slpd, Slpu, Slps, SlpP) (13, 14), and it has recently been shown to have activity in a putative complement pathway (15). In the liver, the major source of Slp, the difference in expression levels of the protein in males and females is due to nuclear factors acting at the transcriptional stage (16). Full expression of Slp in males occurs only after puberty and is dependent upon the presence of testosterone, androgen receptors, and an adult male pattern of growth hormone release (16,17).Due to an apparent tandem duplication, Slp and C4 form a small multigene family (18,19 Slp (24,25).The fascinating observation was made by Brown and Shreffler (26) that in four strains that do not contain hybrid Slp genes (FM, LG, NZB, and PL), the "sex-limitation" is removed in that females also express Slp (26). Expression of Slp was characterized in detail in the strain FM (Slpd); Slp is expressed only after 4 weeks of age in either sex and is expressed in males at higher levels than in f...