Abstract
Background MAGEL2 is one of several genes typically inactivated in the developmental obesity disorder Prader-Willi syndrome (PWS). The physiological consequences of loss of MAGEL2, but without the concurrent loss of other PWS genes, are not well understood. Gene-targeted mutation of Magel2 in mice disrupts circadian rhythm and metabolism causing reduced total activity, reduced weight gain before weaning, and increased adiposity after weaning.Principal FindingsWe now show that loss of Magel2 in mice causes reduced fertility in both males and females through extended breeding intervals and early reproductive decline and termination. Female Magel2-null mice display extended and irregular estrous cycles, while males show decreased testosterone levels, and reduced olfactory preference for female odors.ConclusionsOur results suggest that loss of MAGEL2 contributes to the reproductive deficits seen in people with PWS, and further highlights the role of normal circadian rhythm in the maintenance of fertility.
Highlights
The master pacemaker of circadian rhythm lies in the suprachiasmatic nucleus (SCN) of the hypothalamus
Our results suggest that loss of MAGEL2 contributes to the reproductive deficits seen in people with Prader-Willi syndrome (PWS), and further highlights the role of normal circadian rhythm in the maintenance of fertility
We postulated that the hypothalamic defect that we propose causes abnormalities of circadian rhythm and metabolism in Magel2-null mice could be accompanied by reduced fertility
Summary
The master pacemaker of circadian rhythm lies in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian disruption is often associated with a decrease in reproductive performance. Mutations in key circadian rhythm genes affect female fertility through irregular estrous cycles, pregnancy failure, and reduced survival to weaning in rodents [1,2,3]. Male circadian mutant mice typically have normal reproductive capacity, Bmal deficiency can cause infertility [4] and clockD19 male mice sire smaller litters [5]. A disruption of the circadian output gene VPAC2R causes an age-related decline in male fertility associated with seminiferous tubular degeneration and associated hypospermia [6]. Gene-targeted mutation of Magel in mice disrupts circadian rhythm and metabolism causing reduced total activity, reduced weight gain before weaning, and increased adiposity after weaning
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