title: Heterogeneity in sexual bipotentiality and plasticity of granulosa cells in developing mouse ovaries.
abstract: In mammalian sex determination, SRY directly upregulates the expression of SOX9, the master regulatory transcription factor in Sertoli cell differentiation, leading to testis formation. Without SRY action, the bipotential gonadal cells become pre-granulosa cells, which results in ovarian follicle development. When, where and how pre-granulosa cells are determined to differentiate into developing ovaries, however, remains unclear. By monitoring SRY-dependent SOX9 inducibility (SDSI) in an Sry-inducible mouse system, we were able to identify spatiotemporal changes in the sexual bipotentiality/plasticity of ovarian somatic cells throughout life. The early pre-granulosa cells maintain the SDSI until 11.5 d.p.c., after which most pre-granulosa cells rapidly lose this ability by 12.0 d.p.c. Unexpectedly, we found a subpopulation of the pre-granulosa cells near the mesonephric tissue that continuously retains SDSI throughout fetal and early postnatal stages. After birth, these SDSI-positive pre-granulosa cells contribute to the initial round of folliculogenesis by the secondary follicle stage. In experimental sex reversal of 13.5-d.p.c. ovaries grafted into adult male nude mice, the differentiated granulosa cells re-acquire the SDSI before other signs of masculinization. Our data provide direct evidence of an unexpectedly high sexual heterogeneity of granulosa cells in developing mouse ovaries in a stage- and region-specific manner. Discovery of such sexually bipotential granulosa cells provides a novel entry point to the understanding of masculinization in various cases of XX disorders of sexual development in mammalian ovaries.
authors.affiliation: Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Harikae
authors.forename: Kento
authors.initials: K
authors.lastname: Miura
authors.forename: Mai
authors.initials: M
authors.lastname: Shinomura
authors.forename: Shogo
authors.initials: S
authors.lastname: Matoba
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsunekawa
authors.forename: Masami
authors.initials: M
authors.lastname: Kanai-Azuma
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kurohmaru
authors.forename: Ken-Ichirou
authors.initials: K
authors.lastname: Morohashi
authors.forename: Yoshiakira
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000367:Age Factors; D000818:Animals; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010053:Ovary / Q000166:cytology / Q000254:growth & development / Q000378:metabolism* / Q000637:transplantation; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D019849:Sex Determination Processes / Q000235:genetics; D012733:Sex Differentiation / Q000235:genetics*; D051876:Sex-Determining Region Y Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D055758:SOX9 Transcription Factor; D051876:Sex-Determining Region Y Protein; C527933:Sox9 protein, mouse
keywords: Bipotentiality; Granulosa cells; Ovary; Plasticity; Sox9; Sry