Developmental and reproductive performance in circadian mutant mice.

BACKGROUND Genes underlying circadian rhythm generation are expressed in many tissues. We explore a role for circadian rhythms in the timing and efficacy of mouse reproduction and development using a genetic approach. METHODS We compare fecundity in Clock(Delta19) mutant mice (a dominant-negative protein essential for circadian rhythm activity) and in Vipr2-/- null mutant mice (affecting the generation and output of the circadian rhythm of the hypothalamic suprachiasmatic nucleus) with wild type (WT) litter mates under both a 12 h:12 h light:dark cycle and continuous darkness. RESULTS Uteri from Clock(Delta19) mice show no circadian rhythm and Vipr2-/- mice show a phase-advanced rhythm compared to WT uteri. In neither mutant line were homozygous or heterozygous fetuses lethal. Sexually mature adults of both mutant lines showed mildly reduced male in vivo (but not in vitro) fertility and irregular estrous cycles exacerbated by continuous darkness. However, pregnancy rates and neonatal litter sizes were not affected. The Clock(Delta19) mutant line was distinguishable from the Vipr2-/- null mutant line in showing more peri-natal delivery problems and very poor survival of offspring to weaning. CONCLUSIONS A fully functional central and peripheral circadian clock is not essential for reproduction and development to term, but has critical roles peri-natally and post-partum.