Is female the default sex in humans?
Summary:

The idea that primary sexual determination defaults to female was proposed several decades ago and is primarily based on the observation that, in the absence of Sry, ovarian development takes hold. However, more recent models suggest that both ovary and testis development require complex genetic regulation and neither can really be said to occur by default. Furthermore, maintenance of sexual determination is apparently a life-long process.



Quote from a Review (Yao 2005):


  We have just begun to glimpse into the mechanisms underlying ovarian development. Convincing evidence challenges us to reconsider the existing paradigm that describes ovarian development as a default system. The default concept was first proposed in the early 1950s when Jost performed the groundbreaking experiments to demonstrate mechanisms of sex differentiation of reproductive tracts (Jost, 1947, 1953, 1970). The term “default” was not originally intended to describe the developmental status of the ovary. Instead, it is referred to the female reproductive tract or the Mullerian duct based on the fact that the female reproductive tract forms in both XX and XY individuals in the absence of gonads. Indeed, now it has become evident that early ovarian development is an active process involving intrinsic cell fate decisions and complex crosstalks between germ cells and somatic cells. Most intriguingly, the appearance of testicular structures in XX individuals where Sry and its downstream components are absent further raises the improbable question: Could the testicular development be default after all?




Some Details:

Sex determination in mammals involves the development of a bipotential gonad into either a testis or ovary. Sertoli cell differentiation and thus testis formation is under the control of the regulatory gene Sry (Koopman et al. 1991). The Sry gene product was later shown to upregulate the expression of Sox9, which is key in testis development (Sekido and Lovell-Badge 2008). On the other hand, ovarian development is centered on β-catenin stabilisation by WNT4 signalling, which is thought to inhibit Sox9 expression (Bernard et al. 2012). Because Wnt4 is expressed basally in the genital ridge and testis development apparently depends on Sry expression, the ovarian pathway has often been described as default; in other words, the pathway that the gonad would take in the absence of Sry.

However, ovarian development is in fact an active process requiring the correct balance of many factors, including a transcription factor called forkhead box protein L2 (FOXL2) (Yao 2005). Studies in mice showed that Foxl2 is expressed in the ovary, both during development and in adulthood. Knockout of the gene prevented granulosa cell differentiation during development, leading to ovarian failure (Schmidt et al. 2004) and increased expression of markers for the testis development pathway (Ottolenghi et al. 2005). Furthermore, mutations of this gene are responsible for XX sex reversal in goats (polled intersex syndrome, PIS) (Pailhoux et al. 2001). Taken together, these experiments indicate that Foxl2 is required for ovarian development and that its absence can favour testis formation. 

Many developmental process are dependent on correct timing of gene expression. Sry, particularly, must be expressed within a specific time interval or ovarian development will take hold (Bullejos and Koopman 2005; Hiramatsu et al. 2009). Research by Uhlenhaut et al. (2009), however, shows that this is not necessarily the case for Foxl2 mediated ovarian development, maturation and maintenance. A homozygous floxed Foxl2 mouse strain that expresses Cre under tamoxifen induction allowed conditional knockout of Foxl2. Three weeks after induction, cells of the ovary had transdifferentiated, adopting a morphology and gene expression pattern consistent with Sertoli and Leydig cells (which are normally found in testes). Notably, Sox9 expression increased drastically. Immunostaining showed that, while Foxl2 expression expectedly decreased after Cre induction, the increase in Sox9 was not observed until a day later, indicating that the expression of both is mutually exclusive and that FOXL2 may directly regulate Sox9. 

This research presented a novel model for the maintenance of female ovary differentiation. During primary sex determination in females, activation of WNT4 signalling stabilises β-catenin allowing expression of female specific genes and the inhibition of Sox9 (Bernard et al. 2012). In adulthood, FOXL2 actively represses Sox9 expression in gonad cells, maintaining the granulosa phenotype. A similar model of maintenance has been proposed in males due to evidence that the loss of the transcription factor Dmrt1, which normally represses (and is also repressed by) Foxl2 expression, induces transdifferentiation of male mouse Sertoli cells to granulosa cells (Matson et al. 2011). In the case of both males and females, primary sex determination is not just a process that occurs during development but rather requires active regulation for the duration of adult life. This involves collective antagonism between various female and male sex determining factors, including Foxl2 and Dmrt1, and may dispel the notion that ovarian development occurs by default.



Further Reading:

The Genetics of Sex Determination: Rethinking Concepts and Theories

Genetics of sexual development: a new paradigm (Blecher and Erickson 2007)



References:

Bernard P, Ryan J, Sim H, Czech DP, Sinclair AH, Koopman P, Harley VR. 2012. Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer. Endocrinology 153:901–912.

Blecher SR, Erickson RP. 2007. Genetics of sexual development: a new paradigm. Am J Med Genet A 143A:3054-68.

Bullejos M, Koopman P. 2005. Delayed Sry and Sox9 expression in developing mouse gonads underlies B6-YDOM sex reversal. Dev. Biol. 278:473–481.

Hiramatsu R, Matoba S, Kanai-Azuma M, Tsunekawa N, Katoh-Fukui Y, Kurohmaru M, Morohashi K-I, Wilhelm D, Koopman P, Kanai Y. 2009. A critical time window of Sry action in gonadal sex determination in mice. Development 136:129–138. 

Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. 1991. Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121.

Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D. 2011. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476:101–104.

Ottolenghi C, Omari S, Garcia-Ortiz JE, Uda M, Crisponi L, Forabosco A, Pilia G, Schlessinger D. 2005. Foxl2 is required for commitment to ovary differentiation. Hum. Mol. Genet. 14:2053– 2062.

Pailhoux E, Vigier B, Chaffaux S, Servel N, Taourit S, Furet JP, Fellous M, Grosclaude F, Cribiu EP, Cotinot C, et al. 2001. A 11.7-kb deletion triggers intersexuality and polledness in goats. Nat. Genet. 29:453–458.

Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier A-C, Treier M. 2004. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131:933–942. 

Sekido R, Lovell-Badge R. 2008. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453:930–934. 

Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter NI, et al. 2009. Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation. Cell 139:1130–1142.

Yao HH-C. 2005. The pathway to femaleness: current knowledge on embryonic development of the ovary. Mol. Cell. Endocrinol. 230:87–93.