FOXL2 versus SOX9: A lifelong “battle of the sexes”

Abstract

Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male-specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male-specific genes during development, postnatally and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. Keywords:.F OXL2; ovary determination; ovarian maintenance IntroductionGonadal sex determination is a process that implies a unique decision to make a testis or an ovary out of a bipotential primordium. In most mammals, sex determination is equated with testis determination, whereas ovarian determination has been considered a default process. That is, absence of the testisdetermining factor would automatically lead to the development of an ovary (in appropriate conditions). Recent articles challenge this view and show that in the ovary active mechanisms are required to maintain the differentiated state. [1,2] The bipotential gonad is made up of four presumptive cell lineages: germ cells (which have an extraembryonic origin) and three types of somatic cells. The somatic component involves the supporting cell precursors, which will give rise to Sertoli cells in the male or granulosa cells in the female, the steroidogenic precursors, which differentiate into Leydig cells (male) and theca cells (female), and finally the connective tissue cells yielding other important structures. [3] From a genetic perspective, the SRY gene is pivotal in switching on the testis-determining cascade.[4] Indeed, murine Sry transcripts appear in the presumptive Sertoli cells from 10.5 days postcoitum and for about 2 days, at the right moment for testis determination. [5] In other mammals, including man, SRY is expressed from the period of testis determination until adulthood [6]). It seems now that the main task of Sry/SRY is to directly activate the gene Sox9, which also encodes a transcription factor. Recently a gonad-specific enhancer that mediates testis Sox9 expression, called TESCO, has been identified. [7] Indeed, Sry along with the steroidogenic factor 1 (Sf1) binds to multiple elements within the TESCO. Moreover, mutation, co-transfection, and sex-reversal studies suggest the existence of a positive feedback circuit. First, Sf1 and Sry cooperatively up-regulate Sox9 transcription. Then, Sox9 and Sf1 recognize the enhancer to maintain the expression of the former in the absence of Sr...

Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9

“…2009). Moreover, SOX9 plays a critical role not only in testicular development but also in the maintenance of differentiated status of the testes (Sekido and Lovell‐Badge 2009; Veitia 2010). Thus, testicular regression may be a rare manifestation in patients with SOX9 mutations.…”

“…The discrepancy between the phenotypic severities and the results of in vitro assays can be explained by assuming that some SOX9 target genes other than AMH are more sensitive to defective function of SOX9. Actually, a number of testicular genes are known to be regulated by SOX9 (Sekido and Lovell‐Badge 2009; Veitia 2010). Alternatively, in the developing testis, the p.Arg394Gly and p.Arg437Cys mutations may disrupt the synergic interaction between SOX9 and certain cofactors.…”

“…Alternatively, in the developing testis, the p.Arg394Gly and p.Arg437Cys mutations may disrupt the synergic interaction between SOX9 and certain cofactors. It is known that SOX9 synergizes with other proteins to transactivate target genes (Sekido and Lovell‐Badge 2009; Veitia 2010). On the other hand, we cannot exclude the possibility that genetic variations in other genes or some environmental factors affected sexual development in patients 1 and 2, although mutations in known 46,XY DSD causative genes were excluded in these patients.…”

Sex Determining Mechanisms in Bivalves

“…These results suggest that H. schlegelii and mammals use similar gene regulatory mechanisms to control sex determination (Shi et al 2015). Broadly, male sex determination in mammals is initiated by the expression of Sry (Sex-determining region on Y), which suppresses ovarian promoting genes and activates Sox9 (Sry-box 9), a key element of the testis-determining cascade leading to the activation of Dmrt1 and differentiation of Sertoli cells, whereas female sex determination is initiated by the forkhead box transcription factor FoxL2, β -catenin and Wnt4, which promotes and maintains ovarian development while suppressing Sox9 (Veitia 2010). Because hermaphroditism has already been noted in H. schlegelii, Shi et al (2015) also focused their efforts on searching for key genes known to regulate sex determination in other hermaphroditic model species, such as Caenorhabditis elegans.…”

Mammalian viviparity: a complex niche in the evolution of genomic imprinting

“…Interestingly Sry is a hybrid gene of Dgcr8 and Sox3 (Sato et al, 2010), and serves as the master switch for testes development (Kashimada and Koopman, 2010). It provides the trigger for sex determination by activating Sox9 that not only brings about testes formation but blocks the genetic pathway to the differentiation of ovarian cells (Veitia, 2010).…”