H-2 S region determined polymorphic variants of the C4, Slp, C2, and B complement proteins: A compilation

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 itjections 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 androgenreceptor 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 ii jections. 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.The fourth component of complement (C4) is encoded in the mouse by two genes (C4 and C4-Slp) arranged in tandem (1) in the S region of the H-2 major histocompatibility complex and created by a recent gene duplication (2,3). Notwithstanding the 95% nucleotide (nt) identity throughout their coding (4) and noncoding regions (refs. 3, 5, and 6 and our additional unpublished data), the two genes diverge drastically in their mode of expression in that C4-Slp and not C4 is under stringent developmental and hormonal control. Soon after the discovery of this male-specific serum protein (7), it became clear that the expression of C4-Slp depends on the presence of testosterone. That is, the protein is absent from the serum of female animals or castrated males, where its expression is restored by testosterone treatment (8). As in other mammals, C4 is produced both in liver and in macrophages, but only hepatocytes synthesize Slp. Even though other hepatic genes that display sexually dimorphic regulation have been more intensively studied (9, 10), the C4/C4-Slp system is notable for its more pronounced testosterone response, the array of available regulation variants (11), and lack of the genetic and functional complexity seen in multigene families such as the androgen-inducible a2u globulin in the rat (12) and the homologous mouse major urinary protein (Mup) (13,14). The system acquires additional interest by the existence of trans-acting mutations (15, 37) that override the testosterone requirement of the C4-Slp gene.Functional analyses of the C4-Slp promote...

mentioning

confidence: 99%

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

Georgatsou

Bourgarel

Meo

1993

“…S region of the H-2d or H-2s haplotype only but is constitutively expressed in some wild-type-derived mice (1)(2)(3)(4). Although the SIp gene is thought to be a duplication of the C4 gene with about 95% homology to C4 at both the DNA and the protein level (7,8), the product of this gene is so far considered to be nonfunctional.…”

mentioning

confidence: 99%

Slp is an essential component of an EDTA-resistant activation pathway of mouse complement.

Berg¹,

Démant²,

Aerts³

et al. 1992

“…C4-Slp, the form that is identified by an allotypic antiserum, does not possess all the functional properties of C4 and in fact is hemolytically inactive. The two proteins display considerable structural and quantitative genetic variation (5) and are also distinguished by the regulation and site of expression of their genes. C4-Slp is normally produced only in hepatocytes and its expression is controlled by at least two genetically dissectable mechanisms.…”

mentioning

confidence: 99%

Multiple duplications of complement C4 gene correlate with H-2-controlled testosterone-independent expression of its sex-limited isoform, C4-Slp.

Lévi‐Strauss

Tosi

Steinmetz

et al. 1985

Mouse liver cDNA clones related to the C4 and C4-Slp isoforms of the fourth component of complement differ by few nucleotide changes within a region of substantial divergence from human C4. It is suggested that the mouse C4 gene duplication is an evolutionarily recent event with respect to the time of mammalian radiation. This conclusion is reinforced by the presence of a single C4 gene in the Syrian hamster. Most H-2 haplotypes, including those characterized by an undetectable C4-Slp protein, possess two C4 gene copies which, in contrast to the neighboring factor B, show a marked restriction site polymorphism. The genetic variation of this region is emphasized by the presence in the mouse of a rare "polymorphism" for C4 gene number. Multiple C4-related gene copies characterize those exceptional wild-derived H-2 haplotypes, H-2w7, H-2wl6, and H-2wl9, that determine the expression of the C4-Slp protein in female animals.The S region of the mouse H-2 gene complex was defined by two nonallelic genes encoding the isotypic forms C4 and C4-Slp (sex-limited protein) § of the fourth component of the complement system (1-3).Prior to the discovery of their biological function and the recognition that discrete genes encode the C4 and C4-Slp forms, the two proteins were collectively referred to as the mouse Ss (serum substance) protein, detected by means of xenoantisera (see ref. 4 for a recent review). C4-Slp, the form that is identified by an allotypic antiserum, does not possess all the functional properties of C4 and in fact is hemolytically inactive. The two proteins display considerable structural and quantitative genetic variation (5) and are also distinguished by the regulation and site of expression of their genes. C4-Slp is normally produced only in hepatocytes and its expression is controlled by at least two genetically dissectable mechanisms. By definition, this protein displays sexual dimorphism in that it is androgen controlled and normally undetectable (although testosterone inducible) in females of the standard C4-Slp-positive strains. However, some exceptional wild-derived H-2 haplotypes-namely, H_2w7, H-2w16, and H-2w`9-determine the expression of C4-Slp in both male and female mice (6, 7). In these mice, the protein is produced not only by the liver but also by resident peritoneal macrophages, a cell type that in all strains is the second normal site of C4 expression. This allelism for an androgen-controlled or androgen-independent C4-Slp expression was shown by segregation analysis to involve cis-acting regulatory elements genetically inseparable from the structural gene (8). Alternatively, C4-Slp can be expressed in female mice of certain strains by a second type of androgen-and androgen receptor-independent mechanism, which, however, is not linked to the H-2 complex. This latter phenotype appears to be controlled by transacting and as yet unmapped regulator genes (rsl) able to mimic testosterone action (9). On the other hand, the genetic bases of the lack of C4-Slp even in the males of strains...