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It is assumed that sperm head shape is important for sperm-zona pellucida (ZP) penetration but research has yet to elucidate why. We generated testis expressed 46 (Tex46) knockout mice to investigate the essential roles of TEX46 in mammalian reproduction. We used RT-PCR to demonstrate that Tex46 was expressed exclusively in the male reproductive tract in mice and humans. We created Tex46\u2212\/\u2212 mice using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system and analyzed their fertility. Tex46 null spermatozoa underwent further evaluation using computer-assisted sperm analysis, light microscopy, and ultrastructural microscopy. We used immunoblot analysis to elucidate relationships between TEX46 and other acrosome biogenesis-related proteins. Mouse and human TEX46 are testis-enriched and encode a transmembrane protein which is conserved from amphibians to mammals. Loss of the mouse TEX46 protein causes male sterility primarily due to abnormal sperm head formation and secondary effects on sperm motility. Tex46 null spermatozoa morphologically lack the typical hooked sperm head appearance and fail to penetrate through the ZP. Electron microscopy of the testicular germ cells reveals malformation of the acrosomal cap, with misshapen sperm head tips and the appearance of a gap between the acrosome head and the nucleus. TEX46 is essential for sperm head formation, sperm penetration through the ZP, and male fertility in mice, and is a putative contraceptive target in men.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgae108","type":"journal-article","created":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T08:21:53Z","timestamp":1710231713000},"source":"Crossref","is-referenced-by-count":8,"title":["<i>Tex46<\/i>\n                    knockout male mice are sterile secondary to sperm head malformations and failure to penetrate through the zona pellucida"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8332-3507","authenticated-orcid":false,"given":"Yoshitaka","family":"Fujihara","sequence":"first","affiliation":[{"name":"Department of Advanced Medical Technologies, National Cerebral and Cardiovascular Center , Suita, Osaka 564-8565 , Japan"},{"name":"Research Institute for Microbial Diseases, Osaka University , Suita, Osaka 565-0871 , Japan"},{"name":"Center for Drug Discovery, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4758-5803","authenticated-orcid":false,"given":"Haruhiko","family":"Miyata","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University , Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferheen","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University , Suita, Osaka 565-0871 , Japan"},{"name":"School of Medicine, University of California, Davis , Sacramento, CA 95817 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Larasati","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University , Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Nozawa","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical Technologies, National Cerebral and Cardiovascular Center , Suita, Osaka 564-8565 , Japan"},{"name":"Center for Drug Discovery, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-6217","authenticated-orcid":false,"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University , Suita, Osaka 565-0871 , Japan"},{"name":"Center for Infectious Disease Education and Research (CiDER), Osaka University , Suita, Osaka 565-0871 , Japan"},{"name":"The Institute of Medical Science, The University of Tokyo , Minato-ku, Tokyo 108-8639 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1445-8632","authenticated-orcid":false,"given":"Martin M","family":"Matzuk","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,12]]},"reference":[{"issue":"Suppl 4","key":"2024032723555132100_pgae108-B1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/rda.13552","article-title":"Sperm competition and the evolution of sperm form and function in mammals","volume":"54","author":"Roldan","year":"2019","journal-title":"Reprod Domest Anim"},{"key":"2024032723555132100_pgae108-B2","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1093\/biolre\/ioac037","article-title":"Mysteries and unsolved problems of mammalian fertilization and related topics","volume":"106","author":"Yanagimachi","year":"2022","journal-title":"Biol Reprod"},{"key":"2024032723555132100_pgae108-B3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1093\/humupd\/dml047","article-title":"Globozoospermia revisited","volume":"13","author":"Dam","year":"2007","journal-title":"Hum Reprod Update."},{"key":"2024032723555132100_pgae108-B4","doi-asserted-by":"crossref","first-page":"jcs259206","DOI":"10.1242\/jcs.259206","article-title":"FAM209 associates with DPY19L2, and is required for sperm acrosome biogenesis and fertility in mice","volume":"134","author":"Castaneda","year":"2021","journal-title":"J Cell Sci"},{"key":"2024032723555132100_pgae108-B5","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1111\/andr.13329","article-title":"PDCL2 is essential for sperm acrosome formation and male fertility in mice","volume":"11","author":"Fujihara","year":"2023","journal-title":"Andrology"},{"key":"2024032723555132100_pgae108-B6","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1242\/dev.081778","article-title":"SPACA1-deficient male mice are infertile with abnormally shaped sperm heads reminiscent of globozoospermia","volume":"139","author":"Fujihara","year":"2012","journal-title":"Development"},{"key":"2024032723555132100_pgae108-B7","doi-asserted-by":"crossref","first-page":"6794","DOI":"10.1128\/MCB.01029-07","article-title":"Loss of zona pellucida binding proteins in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis","volume":"27","author":"Lin","year":"2007","journal-title":"Mol Cell Biol."},{"key":"2024032723555132100_pgae108-B8","doi-asserted-by":"crossref","first-page":"dev199644","DOI":"10.1242\/dev.199644","article-title":"FAM71F1 binds to RAB2A and RAB2B and is essential for acrosome formation and male fertility in mice","volume":"148","author":"Morohoshi","year":"2021","journal-title":"Development"},{"key":"2024032723555132100_pgae108-B9","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1093\/biolre\/ioaa040","article-title":"Knockout of serine-rich single-pass membrane protein 1 (Ssmem1) causes globozoospermia and sterility in male mice\u2020","volume":"103","author":"Nozawa","year":"2020","journal-title":"Biol Reprod"},{"key":"2024032723555132100_pgae108-B10","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1242\/dev.077982","article-title":"Absence of Dpy19l2, a new inner nuclear membrane protein, causes globozoospermia in mice by preventing the anchoring of the acrosome to the nucleus","volume":"139","author":"Pierre","year":"2012","journal-title":"Development"},{"key":"2024032723555132100_pgae108-B11","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1172\/JCI36230","article-title":"PICK1 deficiency causes male infertility in mice by disrupting acrosome formation","volume":"119","author":"Xiao","year":"2009","journal-title":"J Clin Investig"},{"key":"2024032723555132100_pgae108-B12","doi-asserted-by":"crossref","first-page":"11211","DOI":"10.1073\/pnas.162027899","article-title":"Lack of acrosome formation in mice lacking a Golgi protein, GOPC","volume":"99","author":"Yao","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024032723555132100_pgae108-B13","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1172\/JCI29224","article-title":"Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility","volume":"116","author":"Yildiz","year":"2006","journal-title":"J Clin Investig"},{"key":"2024032723555132100_pgae108-B14","doi-asserted-by":"crossref","first-page":"e2108777118","DOI":"10.1073\/pnas.2108777118","article-title":"The conserved fertility factor SPACA4\/bouncer has divergent modes of action in vertebrate fertilization","volume":"118","author":"Fujihara","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024032723555132100_pgae108-B15","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1073\/pnas.1917595117","article-title":"Acrosin is essential for sperm penetration through the zona pellucida in 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sperm membrane protein ADAM3 and male fertility [corrected]","volume":"109","author":"Tokuhiro","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024032723555132100_pgae108-B28","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s12522-011-0075-8","article-title":"One-step collagenase method for zona pellucida removal in unfertilized eggs: easy and gentle method for large-scale preparation","volume":"10","author":"Yamatoya","year":"2011","journal-title":"Reprod Med Biol"}],"container-title":["PNAS Nexus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/pnasnexus\/advance-article-pdf\/doi\/10.1093\/pnasnexus\/pgae108\/56944164\/pgae108.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pnasnexus\/article-pdf\/3\/3\/pgae108\/57092408\/pgae108.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pnasnexus\/article-pdf\/3\/3\/pgae108\/57092408\/pgae108.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T19:56:29Z","timestamp":1711569389000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/pnasnexus\/article\/doi\/10.1093\/pnasnexus\/pgae108\/7626722"}},"subtitle":[],"editor":[{"given":"Yannis","family":"Yortsos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,2,29]]},"references-count":28,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,2,29]]}},"URL":"https:\/\/doi.org\/10.1093\/pnasnexus\/pgae108","relation":{},"ISSN":["2752-6542"],"issn-type":[{"value":"2752-6542","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,3]]},"published":{"date-parts":[[2024,2,29]]},"article-number":"pgae108"}}