1. Introduction
In mammals, the ovary has been historically viewed as the default gonadal state, such that in the absence of the Y-chromosome and the sex determining switch gene,
Gonads are comprised of two primary cell types: the somatic cell lineages including the supporting cells and the germ cell lineage which gives rise to the haploid gametes. In testes, the supporting cells consist of the Sertoli cells, which support spermatogenesis, the Leydig cells, which produce testosterone, the peritubular myoid cells, which maintain the structure of the testis cord through the secretion of the basal lamina and the endothelial cells that form the vasculature. In the ovary, the supportings consist of the granulosa cells that support oogenesis, the theca cells that secrete hormones, and the stromal cells will form the connective tissue of the ovary. The germ cells will become the spermatozoa in the testes and oocytes in the ovary. The fate of the germ cells is dependent on the somatic cell environment, (ie, whether they are surrounded by Sertoli or granulosa cells) which, in turn, regulates the appropriate development of the gonad (Koubova et al. 2006; Bowles et al. 2006). Germ cells in the developing ovary will enter into meiotic arrest early in development, while testicular germ cells will arrest in mitosis. The regulation of germ cell entry into meiosis in the ovary is induced by retinoic acid (RA), which activates the expression of Stra8, a cytoplasmic protein required for pre-meiotic DNA replication (Koubova et al. 2006). Early entry into meiosis in males is prevented by expression of
In the male gonad, it is the activation of
2. Molecular control of ovarian differentiation
Since SRY is absent from the XX gonad,
The sex determining
3. Oestrogenic control of ovarian cell fate
Non-mammalian vertebrates trigger sex of the developing fetus in a variety of different ways. These can largely be grouped into either genetic sex determining mechanisms, where a sex specific gene triggers sex, or environmental sex determination, where extrinsic cues determine sex. Oestrogen is known to play an essential role in female sex determination in nonmammalian vertebrates regardless of the sex determining mechanism (Solari 1994; Nakamura 2010). The production of oestrogen in the indifferent gonad is controlled by the expression of
Despite the highly conserved role of oestrogen in nonmammalian vertebrates, its function in the development of the mammalian ovary remains less clear. Interestingly, expression of the oestrogen receptors, which mediate oestrogen actions within the cell, is maintained in the somatic cells of the indifferent gonads of mice, humans, goats, sheep and marsupials indicative of a highly conserved role for oestrogen in the early mammalian gonad (Calatayud et al. 2010). It was a surprising finding then, that oestrogen was not required for initial ovarian development in mice (Couse and Korach 1999). Mice deficient for both the alpha and beta oestrogen receptors or
While mouse studies have been fundamental in developing a basic understanding of gonadal differentiation, there are differences in gene expression, responses to haploinsufficiency of critical genes and, most importantly, in the role of oestrogen in the fetal gonad between mice and other mammals (Wilhelm et al. 2007). Comparative analyses across multiple species can be particularly helpful in isolating critical regulatory networks required for developmental events from those that show species specific variations (Sanchez et al. 2011; Pounds et al. 2011; Crozat et al. 2010; Lu et al. 2009). Outside of the rodent lineage, upregulation of
The ability for oestrogen to direct ovarian development in mammals has been demonstrated in marsupials (Pask et al. 2010; Coveney et al. 2001; Burns 1955). Marsupials have been evolving independently of humans and mice for around 160 million years (Figure 2) (Luo et al. 2011). Sexual differentiation occurs around the time of birth in marsupial, unlike in eutherian mammals where this process occurs
4. Oestrogen blocks male development by modulating SOX9
Administration of oestrogen to genetically male marsupial neonates causes ovarian development of the gonad (Pask et al. 2010; Coveney et al. 2001; Burns 1955). In the presence of oestrogen, key male differentiation genes fail to be up-regulated in the XY gonad and instead, key ovary-promoting genes are upregulated leading to ovarian development (Pask et al. 2010). Oestrogen appears to trigger sex reversal through the exclusion of SOX9 from entering the nucleus in the somatic cells of the developing gonad (Pask et al. 2010). In the absence of nuclear SOX9, Sertoli cell development cannot be initiated and the somatic cells follow a granulosa cell fate (Figure 3).
A conserved role for oestrogen mediating SOX9 action is consistent with several observations in mammals. In mice, Sox9 is able to autoregulate by binding to its own promoter (Sekido and Lovell-Badge 2008). However, despite
Further investigations are needed to determine how oestrogen mediates the subcellular localization of SOX9 within the somatic cells. SOX9 contains two defined nuclear localization signals (NLS) found in the C- and N-termini that are 100% conserved between mouse, human and the wallaby (Pask et al. 2002). Active transport through nucleopore complex is facilitated in part by importin-β, binding directly to the C-terminal NLS (Sim et al. 2008). This binding is enhanced by phosphorylation of SOX9 by phosphokinase A, facilitating increased nuclear import (Malki et al. 2005). The N-terminal NLS binds calmodulin, another factor that facilitates nuclear transport of SOX9 (Argentaro et al. 2003). SOX9 is also subject to SUMOylation and ubiquitination (Sim et al. 2008). SUMOylation has been shown to regulate nucleocytoplasmic trafficking of several proteins while ubiquitination marks proteins for degradation. SUMOylation of SOX9 in COS7 cells has been shown to alter its subnuclear localisation and transcriptional activity (Hattori et al. 2006). Oestrogen may affect one or many of these different pathways to regulate the subcellular localization and activity of SOX9.
5. Conclusions
5.1. A conserved model for determining vertebrate somatic cell fate
While the switch mechanisms that trigger the development of the ovary or testis pathways vary widely among vertebrates, the fundamental control mechanisms regulating somatic cell fate share many commonalities. This suggests a highly conserved and antagonistic relationship between SOX9 and oestrogen driving Sertoli cell and granulosa cell differentiation respectively. In mammals, the somatic cell decision is initially determined by the presence or absence of SRY. When SRY is present,
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