FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD)
- 7 February 2008
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 215 (1), 31-38
- https://doi.org/10.1002/path.2335
Abstract
The transcription factors SOX9 and FOXL2 are required for male and female mammalian gonadal development. We have used specific antibodies to investigate the role of these key proteins in disorders of sex development (DSD), specifically inter-sex states. In normal gonads, SOX9 was found to be restricted to the presence of (pre-)Sertoli cells, while FOXL2 was found in granulosa cells, and in stromal cells interpreted as early ovarian stroma. Both proteins were found within a single patient, when testicular and ovarian development was present; and within the same gonad, when both differentiation lineages were identified, as in ovotesticular DSD (ie hermaphrodite). Especially SOX9 was informative to support the presence of early testicular development (ie seminiferous tubules), expected based on morphological criteria only. In a limited number of DSD cases, FOXL2 was found within reasonably well-developed seminiferous tubules, but double staining demonstrated that it was never strongly co-expressed with SOX9 in the same cell. All seminiferous tubules containing carcinoma in situ (CIS), the malignant counterpart of a primordial germ cell, ie the precursor of type II germ cell tumours of the testis, seminomas and non-seminomas, showed the presence of SOX9 and not FOXL2. In contrast, gonadoblastomas (GBs), the precursor of the same type of cancer, in a dysgenetic gonad, showed expression of FOXL2 and no, or only very low, SOX9 expression. These findings indicate that gonadal differentiation, ie testicular or ovarian, determines the morphology of the precursor of type II germ cell tumours, CIS or GB, respectively. We show that in DSD patients, the formation of either ovarian or/and testicular development can be visualized using FOXL2 and SOX9 expression, respectively. In addition, it initiates a novel way to study the role of the supportive cells in the development of either CIS or GB. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.This publication has 32 references indexed in Scilit:
- Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determinationDevelopmental Biology, 2005
- Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle developmentHuman Molecular Genetics, 2004
- The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenanceDevelopment, 2004
- Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birdsNature Genetics, 1996
- Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related geneNature, 1994
- A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.Proceedings of the National Academy of Sciences of the United States of America, 1993
- Mutational analysis ofSRY in XY femalesHuman Mutation, 1993
- Genetic evidence equating SRY and the testis-determining factorNature, 1990
- Role of mammalian Y chromosome in sex determinationPhilosophical Transactions of the Royal Society of London. B, Biological Sciences, 1988
- Mus poschiavinus Y Chromosome in the C57BL/6J Murine Genome Causes Sex ReversalScience, 1982