title: The APC/C activator FZR1 is essential for meiotic prophase I in mice.
abstract: Fizzy-related 1 (FZR1) is an activator of the Anaphase promoting complex/cyclosome (APC/C) and an important regulator of the mitotic cell division cycle. Using a germ-cell-specific conditional knockout model we examined its role in entry into meiosis and early meiotic events in both sexes. Loss of APC/C(FZR1) activity in the male germline led to both a mitotic and a meiotic testicular defect resulting in infertility due to the absence of mature spermatozoa. Spermatogonia in the prepubertal testes of such mice had abnormal proliferation and delayed entry into meiosis. Although early recombination events were initiated, male germ cells failed to progress beyond zygotene and underwent apoptosis. Loss of APC/C(FZR1) activity was associated with raised cyclin B1 levels, suggesting that CDK1 may trigger apoptosis. By contrast, female FZR1Δ mice were subfertile, with premature onset of ovarian failure by 5 months of age. Germ cell loss occurred embryonically in the ovary, around the time of the zygotene-pachytene transition, similar to that observed in males. In addition, the transition of primordial follicles into the growing follicle pool in the neonatal ovary was abnormal, such that the primordial follicles were prematurely depleted. We conclude that APC/C(FZR1) is an essential regulator of spermatogonial proliferation and early meiotic prophase I in both male and female germ cells and is therefore important in establishing the reproductive health of adult male and female mammals.
authors.affiliation: School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Holt
authors.forename: Victoria
authors.initials: V
authors.lastname: Pye
authors.forename: Evan
authors.initials: E
authors.lastname: Boon
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Stewart
authors.forename: Irene
authors.initials: I
authors.lastname: García-Higuera
authors.forename: Sergio
authors.initials: S
authors.lastname: Moreno
authors.forename: Rubén
authors.initials: R
authors.lastname: Rodríguez
authors.forename: Keith T
authors.initials: KT
authors.lastname: Jones
authors.forename: Eileen A
authors.initials: EA
authors.lastname: McLaughlin
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D064200:Cdh1 Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D049469:Meiotic Prophase I / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009866:Oogenesis / Q000235:genetics / Q000502:physiology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D012727:Sex Characteristics; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000378:metabolism / Q000473:pathology
chemical_list: C534700:Ccnb1 protein, mouse; D064200:Cdh1 Proteins; D056744:Cyclin B1; C577585:Fzr1 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome
keywords: APC/C; CDH1; FZR1; Meiosis; Mouse; Oogenesis; Spermatogenesis