title: Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression.
abstract: Sexually dimorphic expression of a broad array of liver proteins involved in reproduction and xenobiotic metabolism is induced at puberty by sex-specific growth hormone patterns. An additional control of sex-dependent gene expression is conferred by Regulator of sex-limitation (Rsl) alleles. In variant rsl mice, females inappropriately express the male Sex-limited protein, Slp. We recently showed that a panel of male-specific liver genes is repressed by Rsl, accentuating sex differences in a hormone-independent manner. Here we map rsl to a region on Chromosome 13 comprised exclusively of KRAB (Kruppel-associated box) zinc-finger protein (ZFP) genes. Among eight Rsl candidate (Rslcan) genes within the critical genetic interval, the recent duplicates Rslcan-4 and Rslcan-9 both harbor mutations in rsl mice (partial deletion and splice-site inactivation, respectively). Transgenesis with bacterial artificial chromosome (BAC) clones encompassing Rslcan-4 restores male-specific MUP (major urinary protein) expression to rsl mice, whereas a BAC containing Rslcan-9 rescues sex-specific expression of Slp and cytochrome P450 Cyp2d9. Thus, the Rslcan-4 and Rslcan-9 paralogs partitioned regulation of their target genes during evolution. This demonstrates the first biological role for a set of KRAB zinc-finger repressor proteins and reveals the molecular basis of a gene-silencing pathway critical for sexual dimorphism.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109-0618, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Krebs
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Larkins
authors.forename: Ryan
authors.initials: R
authors.lastname: Price
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Tullis
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Miller
authors.forename: Diane M
authors.initials: DM
authors.lastname: Robins
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D020161:Physical Chromosome Mapping; D012097:Repressor Proteins / Q000378:metabolism*; D016335:Zinc Fingers / Q000502:physiology*
chemical_list: D012097:Repressor Proteins; C473932:Rsl protein, mouse