A critical time window ofSryaction in gonadal sex determination in mice

Abstract

In mammals, the Y-linked sex-determining gene Sry cell-autonomously promotes Sertoli cell differentiation from bipotential supporting cell precursors through SRY-box containing gene 9 (Sox9), leading to testis formation. Without Sry action, the supporting cells differentiate into granulosa cells, resulting in ovarian development. However, how Sry acts spatiotemporally to switch supporting cells from the female to the male pathway is poorly understood. We created a novel transgenic mouse line bearing an inducible Sry transgene under the control of the Hsp70.3 promoter. Analysis of these mice demonstrated that the ability of Sry to induce testis development is limited to approximately 11.0-11.25 dpc, corresponding to a time window of only 6 hours after the normal onset of Sry expression in XY gonads. If Sry was activated after 11.3 dpc, Sox9 activation was not maintained, resulting in ovarian development. This time window is delimited by the ability to engage the high-FGF9/low-WNT4 signaling states required for Sertoli cell establishment and cord organization. Our results indicate the overarching importance of Sry action in the initial 6-hour phase for the female-to-male switching of FGF9/WNT4 signaling patterns.

Heterogeneity in sexual bipotentiality and plasticity of granulosa cells in developing mouse ovaries

“…In 12-30 tail somite stage (ts) XX Tg gonads, HS treatment induced ubiquitous SRY expression at 3 hours after HS (supplementary material Fig. S1) (Hiramatsu et al, 2009). In 12-18 ts XX Tg gonads, HS treatment initiates SOX9 expression in most gonadal supporting cells ,9 hours after HS (upper panel in '15ts' of Fig.…”

“…The procedures were approved by the Institutional Animal Care and Use Committee of the Graduate School of Agricultural and Life Sciences in the University of Tokyo (approval ID: P11-502). The inducible Sry transgenic line #44 [with the HSP-Sry (Hsp70.3 promoter-driven murine Sry) transgene; ICR/ C57BL6[B6]-mixed background (Hiramatsu et al, 2009)] and Wnt4 mutant line [129svJ/ICR-mixed background (Vainio et al, 1999)] were used in this study Mizusaki et al, 2003). Male nude mice (8 weeks old; BALB/c, nu/nu, SLC Japan) were used as host mice for the transplantation of fetal ovaries.…”

“…This finding indicates that SRY-dependent Sox9 inducibility is tightly regulated in gonadal precursor cells, and that only supporting cells which correspond to Sry-expressing pre-Sertoli cells in XY gonads achieve a competent state to respond to SRY action in XX gonads. Moreover, we have developed a novel Sry-inducible transgenic (Hsp-Sry Tg) system to induce XX testis sex reversal (Hiramatsu et al, 2009). In this Hsp-Sry Tg system (which we refer to as 'Tg' in this paper), heat shock (HS) treatment induces ectopic Sry expression, leading to transient Sox9 induction in XX Tg supporting cells.…”

“…12-14 tail somites (ts)], Sox9 expression was not only transient but maintained at high levels, resulting in testis formation of XX Tg gonads. After this critical time period, ectopic Sry induction initially induced SOX9 expression in most supporting cells by 11.5 d.p.c., however, Sox9 expression was not maintained, resulting in ovarian differentiation (Hiramatsu et al, 2009). In fetal ovaries at 12.0-12.5 d.p.c., HS-dependent Sry expression did not induce ectopic SOX9 initiation in most ovarian cells, suggesting that the loss of SOX9 inducibility is one of the earliest key events in pre-granulosa cell differentiation.…”

A study of goat SRY protein expression suggests putative new roles for this gene in the developing testis of a species with long‐lasting SRY expression

“…It was also shown elegantly that during testis determination in mice, SRY expression is only required for a 6-hr period (Hiramatsu et al, 2009). During this short time, SRY, with SF1 as a co-factor, induces Sox9 up-regulation in pre-Sertoli cells, thus engaging testis differentiation (Sekido and Lovell-Badge, 2008).…”