TRPM7 and CaV3.2 channels mediate Ca2+ influx required for egg activation at fertilization

The success of mammalian development following fertilization depends on a series of transient increases in egg cytoplasmic Ca 2+ , referred to as Ca 2+ oscillations. Maintenance of these oscillations requires Ca 2+ influx across the plasma membrane, which is mediated in part by T-type, Ca V 3.2 channels. Here we show using genetic mouse models that TRPM7channels are required to support this Ca 2+ influx. Eggs lacking both TRPM7and Ca V 3.2 stop oscillating prematurely, indicating that together they are responsible for the majority of Ca 2+ influx immediately following fertilization. Fertilized eggs lacking both channels also frequently display delayed resumption of Ca 2+ oscillations, which appears to require sperm–egg fusion. TRPM7and Ca V 3.2 channels almost completely account for Ca 2+ influx observed following store depletion, a process previously attributed to canonical store-operated Ca 2+ entry mediated by STIM/ORAI interactions. TRPM7serves as a membrane sensor of extracellular Mg 2+ and Ca 2+ concentrations and mediates the effects of these ions on Ca 2+ oscillation frequency. When bred to wild-type males, female mice carrying eggs lacking TRPM7and Ca V 3.2 are subfertile, and their offspring have increased variance in postnatal weight. These in vivo findings confirm previous observations linking in vitro experimental alterations in Ca 2+ oscillatory patterns with developmental potential and offspring growth. The identification of TRPM7and Ca V 3.2 as key mediators of Ca 2+ influx following fertilization provides a mechanistic basis for the rational design of culture media that optimize developmental potential in research animals, domestic animals, and humans.