title: Focused screening of mitochondrial metabolism reveals a crucial role for a tumor suppressor Hbp1 in ovarian reserve.
abstract: Granulosa cells (GCs) are tightly associated with fertility and the fate of ovarian follicles. Mitochondria are the central executers of apoptosis. However, the genetic basis underlying mitochondrial modulation in GCs during the ovarian development is poorly understood. Here, CRISPR/Cas9-mediated genetic screening was used to identify genes conferring mitochondrial metabolism in human GCs. The results uncovered roles for several tumor suppressors, including HBP1, in the augmentation of mitochondrial function. Focused analysis revealed that high-mobility group (HMG)-box transcription factor 1 (Hbp1) levels regulate mitochondrial biogenesis, which is associated with global changes in transcription including Tfam. The systemic or granulosa-specific but not oocyte-specific ablation of Hbp1 promoted follicle growth and oocyte production, and is associated with the reduced apoptotic signals in mouse GCs. Consistent with increased mitochondrial function and attenuated GC apoptosis, the regulation of Hbp1 conferred substantial protection of ovarian reserve. Thus, the results of the present study provide a critical target to understand the control of the reproductive lifespan.
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: P
authors.initials: P
authors.lastname: Xie
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Qu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: B
authors.initials: B
authors.lastname: Shen
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yanase
authors.affiliation: Department of Biochemistry and Molecular Medicine and Comprehensive Cancer Center, Institute for Pediatric Regenerative Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhou
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.|Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China.
authors.forename: Y
authors.identifier: 0000-0002-6689-7768
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064113:CRISPR-Cas Systems / Q000235:genetics; D002460:Cell Line; D019069:Cell Respiration / Q000235:genetics; D004734:Energy Metabolism; D005260:Female; D005298:Fertility; D005496:Follicular Atresia / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D016147:Genes, Tumor Suppressor; D006107:Granulosa Cells / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006801:Humans; D000073658:Loss of Function Mutation / Q000235:genetics; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009865:Oocytes / Q000378:metabolism; D001678:Organelle Biogenesis; D065851:Ovarian Reserve / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins