{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZona pellucida glycoprotein 4 (ZP4) is a critical constituent of the extracellular matrix that surrounds the mammalian oocyte. As one of the four zona proteins, ZP4 contributes to the structural integrity of the zona pellucida and helps form the intricate matrix that supports oogenesis, fertilization, and early embryo development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its structural role, ZP4 participates in the fertilization process by modulating sperm function. Studies using recombinant as well as native human zona proteins have demonstrated that ZP4 can promote acrosomal exocytosis and modify sperm motility, effects that depend in part on its glycosylation status. In particular, native ZP4 has been shown to induce acrosome reaction via specific signaling pathways—including activation of protein kinase‐A and L‐type Ca2+ channels—differentiating its action from that of related zona glycoproteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, immunization studies targeting a defined ZP4 epitope have confirmed its contribution to triggering acrosomal exocytosis, further underscoring its functional role during gamete interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHowever, the activity of ZP4 appears to be context‐dependent. Transgenic mouse models expressing human ZP4 incorporated into their zona pellucida did not support human sperm binding in isolation, suggesting that while ZP4 plays a key role in modulating acrosomal reaction and sperm motility, it acts in concert with other zona components to facilitate complete gamete recognition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, animal models deficient in ZP4 revealed that absence of this glycoprotein leads to thinning and structural irregularities of the zona pellucida, which severely impairs embryo development and fertility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIntriguingly, although ZP4 is primarily recognized for its reproductive roles, genetic studies have begun to explore its association with non‐reproductive conditions. Investigations in patients with primary open‐angle glaucoma have assessed single nucleotide polymorphisms in the ZP4 gene"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and its exclusive expression in ovarian tissue has also prompted studies linking ZP4 with polycystic ovary syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " These findings highlight the multifaceted biological significance of ZP4 in both fertility and potentially in broader clinical contexts.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "B Meczekalski, R Nawrot, W Nowak, et al. 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