{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:21:14Z","timestamp":1780392074178,"version":"3.54.1"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":43,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Discov."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Structural defects in the zona pellucida (ZP), caused by mutations in\n                    <jats:italic>ZP<\/jats:italic>\n                    genes, are a recognized cause of female infertility; however, their pathogenic mechanisms are not fully understood. Here, we investigated how two distinct ZP defects (complete absence and thinning) compromise fertility using\n                    <jats:italic>Zp1<\/jats:italic>\n                    <jats:sup>mut\/mut<\/jats:sup>\n                    and\n                    <jats:italic>Zp2<\/jats:italic>\n                    <jats:sup>mut\/mut<\/jats:sup>\n                    rat models. We found that ZP deficiency leads to stage-specific oocyte loss during early antral follicle development in vivo and arrests the maturation of fully grown oocytes in vitro, which also exhibit reduced diameter and mitochondrial dysfunction. From the secondary follicle stage onward, granulosa cells showed reduced proliferation, increased apoptosis, and impaired adhesion, culminating in a disorganized cumulus-oocyte complex morphology and disrupted steroidogenesis by the antral stage. Further analysis revealed that the specialized structures for oocyte-somatic cell interaction, namely transzonal projections and oocyte microvilli, were disorganized and reduced in number. This structural disruption was accompanied by a global perturbation of the bidirectional communication and physical adhesion network between the oocyte and its somatic niche, underscoring the ZP\u2019s essential role in organizing this functional microenvironment. At the molecular level, single-cell transcriptomic and protein analyses demonstrated that ZP deficiency induces a thinning of the oocyte cortical actin layer and dysregulation of cytoskeletal dynamics. This was associated with an upregulation of actin-regulating proteins, including TPM4 and ACTN1, and the engagement of focal adhesion-related pathways. The observed cortical actin disorganization provides a plausible mechanistic link to the concurrent abnormalities in microvilli and cell-cell adhesion. Collectively, our results establish the ZP as a critical structural scaffold that ensures oocyte cortical integrity and coordinates the surrounding somatic cell niche. Its disruption leads to a progressive failure in oocyte-somatic cell interaction and support, ultimately resulting in oocyte developmental impairment and loss. This study provides detailed mechanistic insights into the pathogenesis of ZP-related female infertility (particularly empty follicle syndrome).\n                  <\/jats:p>","DOI":"10.1038\/s41420-026-03124-9","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T18:54:01Z","timestamp":1776711241000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zona pellucida is required for oocyte actin cortex and oocyte-somatic cell interactions during oocyte growth"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3759-8718","authenticated-orcid":false,"given":"Shoujing","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixi","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruping","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hualin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8121-9498","authenticated-orcid":false,"given":"Hongmei","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"3124_CR1","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1146\/annurev-biochem-011520-105310","volume":"89","author":"ES Litscher","year":"2020","unstructured":"Litscher ES, Wassarman PM. Zona pellucida proteins, fibrils, and matrix. Annu Rev Biochem. 2020;89:695\u2013715.","journal-title":"Annu Rev Biochem"},{"key":"3124_CR2","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1093\/oxfordjournals.humrep.a136868","volume":"4","author":"J Nichols","year":"1989","unstructured":"Nichols J, Gardner RL. Effect of damage to the zona pellucida on development of preimplantation embryos in the mouse. Hum Reprod. 1989;4:180\u20137.","journal-title":"Hum Reprod"},{"key":"3124_CR3","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1016\/j.cell.2024.02.013","volume":"187","author":"S Nishio","year":"2024","unstructured":"Nishio S, Emori C, Wiseman B, Fahrenkamp D, Dioguardi E, Zamora-Caballero S, et al. ZP2 cleavage blocks polyspermy by modulating the architecture of the egg coat. 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