{
  "abstract": "Fertilization-induced calcium (Ca2+) oscillations are essential for egg activation and embryonic development in mammals. The sperm-specific phospholipase C isoform, PLCζ1, is the primary trigger of these oscillations. Functional and clinical studies have linked mutations or reduced expression of PLCζ1 to male infertility. However, whether PLCζ1 alone accounts for Ca2+ release at fertilization in all mammals remains uncertain. Male mice lacking Plcζ1 exhibit subfertility and reduced litter sizes; their sperm induce delayed, low-frequency Ca2+ oscillations, indicating a compensatory mechanism. Notably, mouse sperm express high levels of PLCδ4, essential for completing the acrosome reaction (AR). In Plcζ1-null sperm, PLCδ4 is upregulated and retained post-AR. These observations suggest a secondary functional role for PLCδ4. Using CRISPR/Cas9 genome editing, we generated Plcδ4 knockout (KO) mice. Plcδ4-null sperm trigger attenuated, delayed Ca2+ oscillations and significantly reduced fertilization rates, indicating that PLCδ4 contributes to but does not independently drive Ca2+ signaling. We therefore generated a Double Knockout (DKO) mouse line lacking both sperm-enriched PLCs. DKO males were sterile, with sperm failing to induce Ca2+ oscillations, and the isolated residual Ca2+ rise was insufficient to activate eggs. These findings reveal that PLCζ1, the primary oscillator, and PLCδ4, a compensatory factor, work cooperatively within a complex, multi-component PLC system that ensures robust fertilization. This work reveals molecular specialization among mammals in initiating the fertilization Ca2+ signals. It has implications for understanding male infertility, improving assisted reproductive technologies, and developing contraceptive strategies.\n\nThe sperm-specific phospholipase C isoform PLCζ1 initiates fertilization Ca2+ oscillations in mammals, yet its loss causes only subfertility. This study shows that while PLCζ1 is the primary oscillator, PLCδ4 is a crucial backup oscillator, constituting a dual-PLC system that ensures robust fertilization in mammals.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts, United States of America",
    "Research and Development, AutoIVF Biotech, Natick, Massachusetts, United States of America",
    "Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, China",
    "Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America",
    "Department of Animal Science, University of Connecticut, Storrs, Connecticut, United States of America",
    "Research and Development, Colossal Biosciences, Dallas, Texas, United States of America",
    "Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina",
    "Animal Models Core Facility, Institute for Applied Life Sciences (IALS), University of Massachusetts, Amherst, Massachusetts, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Neha Gupta"
    },
    {
      "affs": [
        1
      ],
      "name": "Lei Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Hiroki Akizawa"
    },
    {
      "affs": [
        3
      ],
      "name": "Maria G. Gervasi"
    },
    {
      "affs": [
        4
      ],
      "name": "Darya A. Tourzani"
    },
    {
      "affs": [
        5
      ],
      "name": "Pablo E. Visconti"
    },
    {
      "affs": [
        6
      ],
      "name": "Ana Romarowski"
    },
    {
      "affs": [
        7
      ],
      "name": "Mariano Buffone"
    },
    {
      "name": "Wei Cui"
    },
    {
      "name": "Rafael A. Fissore"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/98fvezsfgwaxg.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pbio.3004098",
  "fulltext_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004098",
  "id": "98fvezsfgwaxg",
  "issns": [
    "1545-7885"
  ],
  "landing_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004098",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2743|Sperm and Testicular Function"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Acrosomes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Germ cells/Ova"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Germ cells/Ova/Zygotes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Germ cells/Sperm"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Germ cells/Sperm/Sperm head"
    ],
    [
      "plos",
      "/Biology and life sciences/Developmental biology/Fertilization"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genetic oscillators"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Reproductive physiology/Eggs"
    ]
  ],
  "openalex": "W7225392769",
  "pdf_url": "https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3004098&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-06",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/98fvezsfgwaxg.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:20:24Z",
      "native_id": "10.1371/journal.pbio.3004098",
      "source": "plos",
      "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004098"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Sperm phospholipase C signaling via PLCζ1 and PLCδ4 is essential for Ca²⁺ oscillations and fertility in mice",
  "title_text": "Sperm phospholipase C signaling via PLCζ1 and PLCδ4 is essential for Ca²⁺ oscillations and fertility in mice",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:20:48Z",
  "url": "https://research.draconitic.com/paper/98fvezsfgwaxg",
  "venue": "PLOS Biology",
  "versions": []
}