title: Global but not gonadotrope-specific disruption of Bmal1 abolishes the luteinizing hormone surge without affecting ovulation.
abstract: 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.
authors.affiliation: Douglas Mental Health University Institute and Department of Psychiatry, McGill University, Montreal, Quebec H4H 1R3, Canada.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Chu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Ian D
authors.initials: ID
authors.lastname: Blum
authors.forename: Oliver
authors.initials: O
authors.lastname: Mai
authors.forename: Alexei
authors.initials: A
authors.lastname: Leliavski
authors.forename: Jan
authors.initials: J
authors.lastname: Fahrenkrug
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.forename: Kai-Florian
authors.initials: KF
authors.lastname: Storch
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D030762:Estrous Cycle / Q000502:physiology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000378:metabolism; D015870:Gene Expression; D052681:Gonadotrophs / Q000378:metabolism*; D007150:Immunohistochemistry; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010060:Ovulation / Q000502:physiology*; D010902:Pituitary Gland / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D008156:Luciferases