Battle of the sexes: new insights into genetic pathways of gonadal development.
Sex determination is governed by a series of genetic switches that influence cell fate and differentiation during critical periods of gonadal development. Remarkably, the primordial fetal gonad is bipotential. Therefore, gonadal development provides an excellent opportunity to identify genes involved in differential organogenesis. The identification of the testis-determining gene, SRY (Sex-reversed on the Y), was a pivotal first step towards unraveling this genetic pathway. It is now clear that numerous other genes, in addition to SRY, are necessary for normal testis development. For example, human mutations in a variety of genes (SOX9, WT1, SF1) impair testis development. Murine models provide evidence for additional genes (Lhx9, Emx2, M33, Dmrt, Fgf9). This lecture will highlight insights gleaned from human mutations in the nuclear receptors, SF1 (Steroidogenic Factor1) (NR5A1) and DAX1 (Dosage-sensitive sex reversal, Adrenal hypoplasia congenita, X chromosome) (NR0B1). These studies reveal the exquisite sensitivity of SF1-dependent developmental pathways to gene dosage and function in humans.
Jameson
J Larry
JL
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Achermann
John C
JC
Ozisik
Gokhan
G
Meeks
Joshua J
JJ
D000311:Adrenal Glands / Q000002:abnormalities; D000818:Animals; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics; D012734:Disorders of Sex Development; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D018628:Gene Dosage; D018398:Homeodomain Proteins; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010053:Ovary / Q000254:growth & development; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012097:Repressor Proteins; D012730:Sex Chromosomes / Q000235:genetics; D019849:Sex Determination Processes; D054339:Steroidogenic Factor 1; D013737:Testis / Q000254:growth & development; D014157:Transcription Factors / Q000235:genetics
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C539965:NR0B1 protein, human; C539966:Nr0b1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors