title: FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD).
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.
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Hersmus
authors.forename: N
authors.initials: N
authors.lastname: Kalfa
authors.forename: B
authors.initials: B
authors.lastname: de Leeuw
authors.forename: H
authors.initials: H
authors.lastname: Stoop
authors.forename: J W
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: R
authors.initials: R
authors.lastname: de Krijger
authors.forename: K P
authors.initials: KP
authors.lastname: Wolffenbuttel
authors.forename: S L S
authors.initials: SL
authors.lastname: Drop
authors.forename: R A
authors.initials: RA
authors.lastname: Veitia
authors.forename: M
authors.initials: M
authors.lastname: Fellous
authors.forename: F
authors.initials: F
authors.lastname: Jaubert
authors.forename: L H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis; D002278:Carcinoma in Situ / Q000737:chemistry; D012734:Disorders of Sex Development / Q000196:embryology*; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000032:analysis*; D018507:Gene Expression Regulation, Developmental; D018238:Gonadoblastoma / Q000737:chemistry / Q000196:embryology; D006066:Gonads / Q000737:chemistry / Q000196:embryology*; D006609:High Mobility Group Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000737:chemistry / Q000196:embryology; D010053:Ovary / Q000737:chemistry / Q000196:embryology; D055758:SOX9 Transcription Factor; D013736:Testicular Neoplasms / Q000737:chemistry; D013737:Testis / Q000737:chemistry / Q000196:embryology; D014157:Transcription Factors / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014157:Transcription Factors