The Gonadal Supporting Cell Lineage and Mammalian Sex Determination: The Differentiation of Sertoli and Granulosa Cells

Abstract

The supporting cell lineage plays a crucial role in nurturing the development of germ cells in the adult gonad. Sertoli cells in the testis support the progression of spermatogonial stem cells through meiosis to the production of motile spermatozoa. Granulosa cells, meanwhile, are a critical component of the ovarian follicle that produces the mature oocyte. It is a distinctive feature of the embryonic gonad that at least some of the supporting cells are derived from a single sexually bipotential precursor lineage. It is the commitment of this somatic lineage to either the Sertoli or granulosa cell fate that defines sex determination. In this chapter we review what is known about the key molecules responsible for this lineage decision in the developing mammalian gonads, relying primarily on data from studies of mice and humans. We focus on recent advances in our understanding of the mutually antagonistic interactions of testis- and ovary-determining pathways and their complexity as revealed by genetic analyses. For the sake of simplicity, we will deal with supporting cells in testis and ovary development in separate sections, but numerous points of contact exist between these accounts of gonadogenesis in male and female embryos, primarily due to the aforementioned mutual antagonisms. The final section will offer a brief synthesis of these organ-specific overviews and a summary of the key themes that emerge in this review of supporting cell differentiation in mammalian sex determination.

Disturbed Ovarian Differentiation in XX;SRY-Negative Dogs

“…The most important gene activated by SRY is SOX9. This gene is necessary and sufficient to induce testicular differentiation [39,45]. SOX9 is necessary for the differentiation of Sertoli cells from precursor mesonephric cells, and for the maintenance of the differentiated phenotype, as well as for directing the development of the other somatic testicular cell lineages [12,39,40,42,46].…”

“…Additional contributions of other genes from the SOX family [e.g., SOX3 and SOX10) has also been evidenced [41,49] from the study of DSD conditions. Acting through its receptor (FGFR2), Fgf9 suppresses the Wnt4 signaling pathway, inhibiting the mechanism that controls the ovarian differentiation [40,44,45,50]. Moreover, Fgf9 sustains SOX9 expression through a positive feedback loop [34].…”

“…WNT4 (Wingless-type MMTV integration site 4) requires several co-activators to prompt the ovarian differentiation, the RSPO1 (R-spondin ligand 1) representing an important molecule of the canonical Wnt signaling cascade [35,45]. The activation of the Wnt4 signaling cascade leads to the accumulation of -catenin, which becomes available to translocate to the nucleus and trigger diverse transcriptional factors [50].…”

“…It has been proposed that the loss of another determining ovarian differentiation gene-FOXL2 (Forkhead Box L2) [37,45]-may originate an up-regulation of the pro-testis pathway mediated by SOX9 [57], and the transdifferentiation of granulosa cells into Sertoli cells in the adult mouse ovary [58]. The FOXL2 pathway, however, seems to be independent of the WNT signaling cascade, albeit with the same aim-orchestrate the ovary differentiation.…”

“…Since the response to the loss of Foxl2 signaling seems to vary between species, and also with the moment of occurrence, it has been suggested that it may be more important for the maintenance of the female gonad structure than to its differentiation from the bipotential gonad [35,60]. Disturbed expression of Foxl2 has been associated with ovarian dysgenesis, blockage of follicle formation and disruption of follicle activation in human and mice, besides the ovary-totestis sex reversal in some species such as goats [45,50,57]. Species differences regarding the moment of gonadal female-to-male sex reversal may relate to the physiologic ability for estrogen secretion by the fetal gonads.…”