Edwina Sutton

Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

≤ 0.1%, in the absence of TKI therapy. This is termed treatment-free remission (TFR). Identifying clinical and biological predictors of TFR has become a major goal in CML. In this review, we discuss clinical predictors of TFR, including features at diagnosis, molecular response and kinetics, depth and duration of molecular response, and dose reduction prior to TKI cessation in determining TFR success. We also discuss advances in highly sensitive Minimal Residual Disease (MRD) assays, consider the genomic profile of CML patients and review the role of the immune environment in sustaining TFR.

Sox3 is expressed in the progenitor cells of the embryonic CNS and functions as a dosage‐dependent regulator of CNS development in mice and man. To further investigate the role of SOX3, we generated transgenic mice using a Sox3 genomic BAC fragment. Unexpectedly, progeny from one line (termed Sex reversed (Sr)) exhibited a markedly distorted sex ratio in favour of male offspring. Analysis of the reproductive tract in adult sex‐reversed animals indicated that all male‐specific structures were present, indicating complete XX male sex reversal. Transgene expression analysis in Sr embryos demonstrated that Sox3 is ectopically upregulated in the primordium of XX and XY gonads during sex determination due to a position effect. Importantly, morphological, gene expression and co‐transfection studies indicate that SOX3 induces testis differentiation in Sr embryonic gonads by activation of Sox9 in a mechanism analogous to that used by the Y‐linked sex determining gene Sry . Together, these data suggest that SOX3 and SRY proteins are functionally interchangeable in sex determination and provide support for the notion that Sry evolved from Sox3 via a regulatory mutation that led to its de novo expression in the early gonad.