title: PUMA regulates germ cell loss and primordial follicle endowment in mice.
abstract: The number of primordial follicles initially established within the ovary is influenced by the extent of germ cell death during foetal ovarian development, but the mechanisms that mediate this death have not been fully uncovered. In this study, we identified BBC3 (PUMA) (p53 upregulated modulator of apoptosis, also known as BCL2-binding component 3), a pro-apoptotic BH3-only protein belonging to the BCL2 family, as a critical determinant of the number of germ cells during ovarian development. Targeted disruption of the Bbc3 gene revealed a significant increase in the number of germ cells as early as embryonic day 13.5. The number of germ cells remained elevated in Bbc3(-/-) female mice compared with WT female mice throughout the remainder of embryonic and early postnatal life, resulting in a 1.9-fold increase in the number of primordial follicles in the ovary on postnatal day 10. The increase in the number of germ cells observed in the ovaries of Bbc3(-/-) mice could not be attributed to the altered proliferative activity of germ cells within the ovaries. Furthermore, BBC3 was found to be not required for the massive germ cell loss that occurs during germ cell nest breakdown. Our data indicate that BBC3 is a critical regulator of germ cell death that acts during the migratory phase of oogenesis or very soon after the arrival of germ cells in the gonad and that BBC3-mediated cell death limits the number of primordial follicles established in the initial ovarian reserve.
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, AustraliaMIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Myers
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, AustraliaMIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: F Hamish
authors.initials: FH
authors.lastname: Morgan
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Liew
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Nadeen
authors.initials: N
authors.lastname: Zerafa
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Thilini Upeksha
authors.initials: TU
authors.lastname: Gamage
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Mai
authors.initials: M
authors.lastname: Sarraj
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Michele
authors.initials: M
authors.lastname: Cook
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ileana
authors.initials: I
authors.lastname: Kapic
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, AustraliaMIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Antony
authors.initials: A
authors.lastname: Sutherland
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, AustraliaMIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, AustraliaMIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jock K
authors.initials: JK
authors.lastname: Findlay
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kerr
authors.affiliation: MIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, AustraliaMIMR-PHI Institute of Medical Research27-31 Wright Street, Clayton, Victoria 3168, AustraliaDepartment of Anatomy and Developmental BiologyMonash University, Clayton, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, AustraliaDepartment of Medical BiologyThe University of Melbourne, Melbourne, Victoria, Australia Karla.Hutt@princehenrys.org.
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Hutt
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D025521:Tumor Suppressor Proteins