Embryogenesis begins with a zygote, a single cell with two pronuclei that separately enclose maternal and paternal chromosomes. The functional significance of the separation of parental chromosomes into distinct pronuclei remains unexplored, despite the fact that one-pronuclear biparental zygotes are used clinically. Here, using a combination of mouse zygote manipulation, quantitative imaging and theoretical approaches, we show a cytoplasm-mediated competition mechanism between separate parental pronuclei that ensures developmental potential. This mechanism limits pronuclear volume and prevents epigenetic mark dysregulation, including loss of trimethylated histones. One-pronuclear biparental zygotes lack this mechanism, resulting in a reduced rate of development to term. This low developmental potential can be rescued by competition-based or drug-based restoration of epigenetic marks. This study provides a spatial mechanism linking fertilization to the establishment of the full developmental potential for the next generation, highlighting caveats in clinical use of one-pronuclear biparental zygotes.
Hirohisa Kyogoku, Mitsusuke Tarama, Masahiro Matsuwaka, Tappei Mishina, Akihito Harada, Reiko Nakagawa, Mami Kumon, Yoshihiro Shimizu, Yasuyuki Ohkawa, Tatsuo Shibata, Azusa Inoue, Tomoya S Kitajima (2026) Cytoplasmic competition between separate parental pronuclei in zygotes., Nature
Published in April 29, 2026 (Electronic publication in April 29, 2026, midnight )
(Abstract) Embryogenesis begins with a zygote-a single cell with two pronuclei that separately enclose maternal and paternal chromosomes. The functional significance of the separation of parental chromosomes into distinct pronuclei remains unexplored, despite the fact that one-pronuclear biparental zygotes are used clinically(1-3). Here, using a combination of mouse zygote manipulation, quantitative imaging and theoretical approaches, we show a cytoplasm-mediated competition mechanism between separate parental pronuclei that ensures developmental potential. This mechanism limits pronuclear volume and prevents epigenetic mark dysregulation, including loss of trimethylated histones. One-pronuclear biparental zygotes lack this mechanism, resulting in a reduced rate of development to term. This low developmental potential can be partially rescued by competition-based or drug-based restoration of epigenetic marks. This study provides a spatial mechanism linking fertilization to the establishment of the full developmental potential for the next generation, highlighting caveats in clinical use of one-pronuclear biparental zygotes.