Global But Not Gonadotrope-Specific Disruption of Bmal1 Abolishes the Luteinizing Hormone Surge Without Affecting Ovulation

• Published in: Endocrinology (Philadelphia) 2013-08, Vol.154 (8), p.2924-2935
• Main Authors: Chu, Adrienne, Zhu, Lei, Blum, Ian D, Mai, Oliver, Leliavski, Alexei, Fahrenkrug, Jan, Oster, Henrik, Boehm, Ulrich, Storch, Kai-Florian
• Format: Article
• Language: English
• Subjects: Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Biological and medical sciences; Biological clocks; BMAL1 protein; Circadian Clocks - genetics; Circadian Clocks - physiology; Circadian rhythm; Circadian rhythms; Cryptochromes - genetics; Cryptochromes - metabolism; Estrous Cycle - physiology; Estrus cycle; Female; Females; Follicle Stimulating Hormone - blood; Follicle Stimulating Hormone - metabolism; Follicle-stimulating hormone; Fundamental and applied biological sciences. Psychology; Gene Expression; Gonadotrophs - metabolism; Gonadotropin-releasing hormone; Immunohistochemistry; Luciferases - genetics; Luciferases - metabolism; Luminescent Measurements - methods; Luteinizing hormone; Luteinizing Hormone - blood; Luteinizing Hormone - metabolism; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Ovulation; Ovulation - physiology; Pituitary; Pituitary (anterior); Pituitary Gland - metabolism; Pituitary Gland - physiology; Reverse Transcriptase Polymerase Chain Reaction; Suprachiasmatic nucleus; Time Factors; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-1080

Although there is evidence for a circadian regulation of the preovulatory LH surge, the contributions of individual tissue clocks to this process remain unclear. We studied female mice deficient in the Bmal1 gene (Bmal1−/−), which is essential for circadian clock function, and found that they lack the proestrous LH surge. However, spontaneous ovulation on the day of estrus was unaffected in these animals. Bmal1−/− females were also deficient in the proestrous FSH surge, which, like the LH surge, is GnRH-dependent. In the absence of circadian or external timing cues, Bmal1−/− females continued to cycle in constant darkness albeit with increased cycle length and time spent in estrus. Because pituitary gonadotropes are the source of circulating LH and FSH, we assessed hypophyseal circadian clock function and found that female pituitaries rhythmically express clock components throughout all cycle stages. To determine the role of the gonadotrope clock in the preovulatory LH and FSH surge process, we generated mice that specifically lack BMAL1 in gonadotropes (GBmal1KO). GBmal1KO females exhibited a modest elevation in both proestrous and baseline LH levels across all estrous stages. BMAL1 elimination from gonadotropes also led to increased variability in estrous cycle length, yet GBmal1KO animals were otherwise reproductively normal. Together our data suggest that the intrinsic clock in gonadotropes is dispensable for LH surge regulation but contributes to estrous cycle robustness. Thus, clocks in the suprachiasmatic nucleus or elsewhere must be involved in the generation of the LH surge, which, surprisingly, is not required for spontaneous ovulation.