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Effect of Deletion of the Circadian Gene Bmal1 in Neuromedin-S Neurons on Female Fertility


The female reproductive system is coupled with circadian rhythms, and circadian disruption is associated with decreased reproductive capacity. For example, the preovulatory luteinizing hormone (LH) surge is temporally regulated. In the hypothalamus, the suprachiasmatic nucleus (SCN) sends projections to the kisspeptin and gonadotropin-releasing hormone (GnRH) neurons to properly synchronize their endogenous clocks. Previous studies have demonstrated that the whole-body deletion of Bmal1, a critical molecular clock gene, in female mice results in no LH surge and infertility. However, the site of action of Bmal1 in the LH surge is unknown. Recently, we demonstrated that mice with a conditional Bmal1 knockout in either kisspeptin or GnRH neurons were fertile, with a normal LH surge. Therefore, we hypothesized that Bmal1 in the SCN would be critical for female reproduction. Neuromedin-S (NMS) is a neuropeptide abundantly expressed in the SCN, and in nearly all VIP and AVP expressing neurons, which send projections to GnRH and kisspeptin neurons, respectively. Bmal1 knockout in NMS neurons resulted in loss of behavioral circadian rhythm under constant darkness, verifying clock disruption in the SCN. Nevertheless, ovariectomized Bmal1fl/fl-NMSCre mice showed an LH surge at the appropriate time when given exogenous estradiol, and with kisspeptin administration. They had normal estrous cyclicity and were fertile when mated with a wildtype male. Thus, despite Bmal1fl/fl-NMSCre female mice showing arrhythmic behavior, they are fertile. However, preliminary results indicate that ovaries in constant darkness showed less numbers of corpora lutea meaning decreased ovulation. These data suggest that the reproductive neurons, the endogenous clock or SCN temporal regulation is sufficient for fertility.

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