Conditional deletion of Bmal1 in ovarian theca cells disrupts ovulation in female mice

Amanda L. Mereness, Zachary C. Murphy, Andrew C. Forrestel, Susan Butler, Che Myong Ko, Jo Anne S. Richards, Michael T. Sellix

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)913-927
Number of pages15
JournalEndocrinology
Volume157
Issue number2
DOIs
StatePublished - Feb 2016

ASJC Scopus subject areas

  • Endocrinology

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    Mereness, A. L., Murphy, Z. C., Forrestel, A. C., Butler, S., Ko, C. M., Richards, J. A. S., & Sellix, M. T. (2016). Conditional deletion of Bmal1 in ovarian theca cells disrupts ovulation in female mice. Endocrinology, 157(2), 913-927. https://doi.org/10.1210/en.2015-1645