TY - JOUR
T1 - Human SRY inhibits β-catenin-mediated transcription
AU - Bernard, Pascal
AU - Sim, Helena
AU - Knower, Kevin
AU - Vilain, Eric
AU - Harley, Vincent
PY - 2008/7/1
Y1 - 2008/7/1
N2 - 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/β-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/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCF-dependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-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 β-catenin involves neither DNA-binding nor transactivation functions of SRY. β-Catenin and SRY interact in vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.
AB - 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/β-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/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCF-dependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-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 β-catenin involves neither DNA-binding nor transactivation functions of SRY. β-Catenin and SRY interact in vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.
KW - β-Catenin
KW - Rspo1
KW - Sex determination
KW - Sex reversal
KW - SRY
KW - Wnt signaling
UR - http://www.scopus.com/inward/record.url?scp=51249093042&partnerID=8YFLogxK
U2 - 10.1016/j.biocel.2008.06.006
DO - 10.1016/j.biocel.2008.06.006
M3 - Article
C2 - 18598779
AN - SCOPUS:51249093042
SN - 1357-2725
VL - 40
SP - 2889
EP - 2900
JO - International Journal of Biochemistry & Cell Biology
JF - International Journal of Biochemistry & Cell Biology
IS - 12
ER -