title: Mcl-1 is a key regulator of the ovarian reserve.
abstract: A majority of ovarian follicles are lost to natural death, but the disruption of factors involved in maintenance of the oocyte pool results in a further untimely follicular depletion known as premature ovarian failure. The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia-1 (MCL-1) has a pro-survival role in various cell types; however, its contribution to oocyte survival is unconfirmed. We present a phenotypic characterization of oocytes deficient in Mcl-1, and establish its role in maintenance of the primordial follicle (PMF) pool, growing oocyte survival and oocyte quality. Mcl-1 depletion resulted in the premature exhaustion of the ovarian reserve, characterized by early PMF loss because of activation of apoptosis. The increasingly diminished surviving cohort of growing oocytes displayed elevated markers of autophagy and mitochondrial dysfunction. Mcl-1-deficient ovulated oocytes demonstrated an increased susceptibility to cellular fragmentation with activation of the apoptotic cascade. Concomitant deletion of the pro-apoptotic Bcl-2 member Bcl-2-associated X protein (Bax) rescued the PMF phenotype and ovulated oocyte death, but did not prevent the mitochondrial dysfunction associated with Mcl-1 deficiency and could not rescue long-term breeding performance. We thus recognize MCL-1 as the essential survival factor required for conservation of the postnatal PMF pool, growing follicle survival and effective oocyte mitochondrial function.
authors.affiliation: 1] Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada [2] Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Omari
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Waters
authors.affiliation: 1] Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada [2] Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Naranian
authors.affiliation: 1] Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada [2] Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada.
authors.forename: A L
authors.initials: AL
authors.lastname: Perumalsamy
authors.affiliation: Department of Obstetrics and Gynecology, Washington University in St. Louis, 660S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chi
authors.affiliation: 1] Centre for Fertility and Reproductive Health, Mount Sinai Hospital, 250 Dundas Street, Toronto, Ontario M5T 2Z5, Canada [2] Department of Obstetrics and Gynecology, University of Toronto, 92 College Street, Toronto, Ontario M5G 1L4, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Greenblatt
authors.affiliation: Department of Obstetrics and Gynecology, Washington University in St. Louis, 660S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Moley
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, MS 340, Room D4063D, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Opferman
authors.affiliation: 1] Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada [2] Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada [3] Department of Obstetrics and Gynecology, University of Toronto, 92 College Street, Toronto, Ontario M5G 1L4, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Jurisicova
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000502:physiology*; D009865:Oocytes / Q000502:physiology; D065851:Ovarian Reserve / Q000502:physiology*
chemical_list: C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein