title: Establishment of testis-specific SOX9 activation requires high-glucose metabolism in mouse sex differentiation.
abstract: In mouse sex differentiation, SRY promotes Sertoli cell differentiation via SOX9 action, resulting in testis formation. SRY/SOX9 also initiates various testis-specific morphogenic events including glycogenesis in pre-Sertoli cells, suggesting the importance of glucose storage for certain SRY/SOX9-downstream events in gonadal sex determination. However, it remains unclear which cell types and what molecular/cellular events require sex-dimorphic high-energy metabolic rate. Here we show that the establishment of SOX9 activation itself is a metabolically active process with sex-dimorphic high-energy requirements in gonadal sex differentiation. The glucose-deprivation and metabolic rescue experiments using genital ridge cultures of the XY/XX-wildtype and XX/Sry transgenic embryos demonstrated that, among the various somatic cell types, pre-Sertoli cells are the most sensitive to glucose starvation despite the differences between XX/Sry and XY genotypes. Moreover, our data showed that, in developing pre-Sertoli cells, the high-glucose metabolic state is required for the establishment of SOX9 expression through an ECM (extracellular matrix)-mediated feed-forward pathway. In contrast, the expression of SRY, SF1/Ad4Bp, GATA4 and WT1, as well as initiation of early SOX9 expression, is properly maintained in the glucose-deprived condition. Therefore, our results imply the metabolic importance of the high-glucose condition for the establishment of SOX9 activation in testis differentiation.
authors.affiliation: Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Matoba
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Masami
authors.initials: M
authors.lastname: Kanai-Azuma
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsunekawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Harikae
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kurohmaru
authors.forename: Yoshiakira
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D055758:SOX9 Transcription Factor / Q000502:physiology*; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012733:Sex Differentiation / Q000187:drug effects / Q000502:physiology*; D013737:Testis / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D006003:Glycogen; D005947:Glucose