Establishment of testis-specific SOX9 activation requires high-glucose metabolism in mouse sex differentiation.
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.
Matoba
Shogo
S
Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
Hiramatsu
Ryuji
R
Kanai-Azuma
Masami
M
Tsunekawa
Naoki
N
Harikae
Kyoko
K
Kawakami
Hayato
H
Kurohmaru
Masamichi
M
Kanai
Yoshiakira
Y
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
D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D006003:Glycogen; D005947:Glucose