Human SRY inhibits beta-catenin-mediated transcription.
In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA-binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/beta-catenin-signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/beta-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed beta-catenin-mediated TCF-dependent gene activation in the presence of a specific GSK3beta inhibitor or an activated beta-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of beta-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit beta-catenin; surprisingly four SRY sex reversed mutants with defective DNA-binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of beta-catenin involves neither DNA-binding nor transactivation functions of SRY. beta-Catenin and SRY interact in vitro and SRY expression triggered beta-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits beta-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.
Bernard
Pascal
P
Prince Henry's Institute of Medical Research, Human Molecular Genetics Laboratory, Monash Medical Centre, Clayton, Australia.
Sim
Helena
H
Knower
Kevin
K
Vilain
Eric
E
Harley
Vincent
V
D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D012734:Disorders of Sex Development; D005260:Female; D024282:Genes, sry; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D015398:Signal Transduction; D014158:Transcription, Genetic; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051155:Wnt1 Protein; D051176:beta Catenin