title: Positional cloning of the PIS mutation in goats and its impact on understanding mammalian sex-differentiation.
abstract: In goats, the PIS (polled intersex syndrome) mutation is responsible for both the absence of horns in males and females and sex-reversal affecting exclusively XX individuals. The mode of inheritance is dominant for the polled trait and recessive for sex-reversal. In XX PIS-/- mutants, the expression of testis-specific genes is observed very precociously during gonad development. Nevertheless, a delay of 4-5 days is observed in comparison with normal testis differentiation in XY males. By positional cloning, we demonstrate that the PIS mutation is an 11.7-kb regulatory-deletion affecting the expression of two genes, PISRT1 and FOXL2 which could act synergistically to promote ovarian differentiation. The transcriptional extinction of these two genes leads, very early, to testis-formation in XX homozygous PIS-/- mutants. According to their expression profiles and bibliographic data, we propose that FOXL2 may be an ovary-differentiating gene, and the non-coding RNA PISRT1, an anti-testis factor repressing SOX9, a key regulator of testis differentiation. Under this hypothesis, SRY, the testis-determining factor would inhibit these two genes in the gonads of XY males, to ensure testis differentiation.
authors.affiliation: Laboratoire de biologie du développement et reproduction, Institut national de la recherche agronomique, 78352 Jouy-en-Josas Cedex, France. pailhoux@jouy.inra.fr
authors.forename: Eric
authors.initials: E
authors.lastname: Pailhoux
authors.forename: Bernard
authors.initials: B
authors.lastname: Vigier
authors.forename: Laurent
authors.initials: L
authors.lastname: Schibler
authors.forename: Edmond P
authors.initials: EP
authors.lastname: Cribiu
authors.forename: Corinne
authors.initials: C
authors.lastname: Cotinot
authors.forename: Daniel
authors.initials: D
authors.lastname: Vaiman
mesh_terms: D000818:Animals; D022202:Chromosomes, Artificial, Bacterial; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012734:Disorders of Sex Development; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D008040:Genetic Linkage; D006041:Goats / Q000196:embryology / Q000235:genetics*; D006609:High Mobility Group Proteins / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D010053:Ovary / Q000196:embryology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D055758:SOX9 Transcription Factor; D012733:Sex Differentiation / Q000235:genetics*; D013737:Testis / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; D014157:Transcription Factors