Reproductive performance in female Clock Delta19 mutant mice.

The relationship between circadian rhythmicity and rodent reproductive cyclicity is well established, but the impact of disrupted clock gene function on reproduction has not been well established. The present study evaluated the reproductive performance of mice carrying the Clock(Delta19) mutation that were either melatonin deficient (Clock(Delta19/Delta19)) or had the capacity to synthesise melatonin reinstated (Clock(Delta19/Delta19)+MEL). The Clock(Delta19/Delta19) mice took 2-3 days longer to mate, and to subsequently deliver pups, than their control line. The melatonin-competent mutants had a smaller, but still significant (P < 0.05), delay. The Clock(Delta19) mutation resulted in smaller median litter sizes compared with control lines (seven v. eight pups; P < 0.05), whereas melatonin proficiency reversed this difference. Survival to weaning was 84% and 80% for the Clock(Delta19/Delta19) and Clock(Delta19/Delta19)+MEL lines, respectively, compared with 94-96% for the two control lines. The Clock(Delta19/Delta19) mutants became behaviourally arrhythmic in constant darkness but, despite this, seven of seven became pregnant when paired with males after at least 14 days of constant darkness (five of seven within 4 days of pairing). In the Clock(Delta19/Delta19)+MEL mice, seven of 15 became arrhythmic in constant darkness but still became pregnant. The seven mice that free ran for at least 14 days in constant darkness with a period of 27.1 h also became pregnant. The present study has demonstrated that the Clock(Delta19) mutation has significant, but subtle, effects on reproductive performance. The reintroduction of melatonin competency and/or other genes as a result of crosses with CBA mice reduced the impact of the mutation further. It would appear that redundancy in genes in the circadian system allows the reproductive cyclicity to persist in mice, albeit at a suboptimal level.