title: Conditional Deletion of Bmal1 in Ovarian Theca Cells Disrupts Ovulation in Female Mice.
abstract: Rhythmic events in female reproductive physiology, including ovulation, are tightly controlled by the circadian timing system. The molecular clock, a feedback loop oscillator of clock gene transcription factors, dictates rhythms of gene expression in the hypothalamo-pituitary-ovarian axis. Circadian disruption due to environmental factors (eg, shift work) or genetic manipulation of the clock has negative impacts on fertility. Although the central pacemaker in the suprachiasmatic nucleus classically regulates the timing of ovulation, we have shown that this rhythm also depends on phasic sensitivity to LH. We hypothesized that this rhythm relies on clock function in a specific cellular compartment of the ovarian follicle. To test this hypothesis we generated mice with deletion of the Bmal1 locus in ovarian granulosa cells (GCs) (Granulosa Cell Bmal1 KO; GCKO) or theca cells (TCs) (Theca Cell Bmal1 KO; TCKO). Reproductive cycles, preovulatory LH secretion, ovarian morphology and behavior were not grossly altered in GCKO or TCKO mice. We detected phasic sensitivity to LH in wild-type littermate control (LC) and GCKO mice but not TCKO mice. This decline in sensitivity to LH is coincident with impaired fertility and altered patterns of LH receptor (Lhcgr) mRNA abundance in the ovary of TCKO mice. These data suggest that the TC is a pacemaker that contributes to the timing and amplitude of ovulation by modulating phasic sensitivity to LH. The TC clock may play a critical role in circadian disruption-mediated reproductive pathology and could be a target for chronobiotic management of infertility due to environmental circadian disruption and/or hormone-dependent reprogramming in women.
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Mereness
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Murphy
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Forrestel
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Susan
authors.initials: S
authors.lastname: Butler
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: CheMyong
authors.initials: C
authors.lastname: Ko
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: JoAnne S
authors.initials: JS
authors.lastname: Richards
authors.affiliation: Department of Medicine (A.L.M., Z.C.M., A.C.F., S.B., M.T.S.), Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Comparative Biosciences (C.K.), College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology (J.S.R.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Sellix
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000235:genetics*; D015870:Gene Expression; D006107:Granulosa Cells / Q000378:metabolism*; D007246:Infertility / Q000235:genetics; D007986:Luteinizing Hormone / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D006080:Ovarian Follicle / Q000378:metabolism; D010053:Ovary / Q000033:anatomy & histology; D010060:Ovulation / Q000235:genetics*; D010062:Ovulation Induction; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011962:Receptors, FSH / Q000235:genetics / Q000378:metabolism; D011974:Receptors, LH / Q000235:genetics*; D013799:Theca Cells / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D011962:Receptors, FSH; D011974:Receptors, LH; D007986:Luteinizing Hormone; D056926:CLOCK Proteins; C538944:Clock protein, mouse