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Spermatozoa are ejaculated and migrate from the uterus to the oviducts to fuse with oocytes. Although over 2000 genes are expressed abundantly in mouse testes, the genes responsible for male fertility are not yet fully clarified. Here, we focused on two testis-enriched serine protease genes, Serine protease (Prss) 51 and Prss55, which overlap their gene loci partially in both mice and humans. To characterize their functions in male fertility, we first generated Prss51 and Prss55 double knockout (DKO) mice by CRISPR\/Cas9 system and found that the DKO mice were sterile. DKO spermatozoa exhibit impaired migration from the uterus to the oviduct and impaired ability to bind the zona pellucida (ZP) of oocytes. Moreover, a sperm membrane protein, ADAM3 (a disintegrin and metalloprotease 3), which plays a role in sperm migration through uterotubal junction (UTJ) and sperm\u2013ZP binding, disappeared in the DKO spermatozoa from the epididymis. We next generated single knockout (KO) mice lacking Prss51 and found that Prss51 KO mice are fertile. We also generated single KO mice lacking Prss55 and found that Prss55 KO mice phenocopy the DKO mice, demonstrating impaired sperm migration and sperm\u2013ZP binding and a severe defect in fertility. We conclude that Prss55, but not Prss51, is required for male fertility in mice, by stabilizing ADAM3 protein for efficient sperm\u2013UTJ migration and sperm\u2013ZP binding. Our findings have implications for understanding additional genetic causes of the idiopathic male infertility and for the development of male or female contraceptives.<\/jats:p>","DOI":"10.1093\/biolre\/ioaa041","type":"journal-article","created":{"date-parts":[[2020,4,17]],"date-time":"2020-04-17T13:26:52Z","timestamp":1587130012000},"page":"223-234","source":"Crossref","is-referenced-by-count":35,"title":["Prss55 but not Prss51 is required for male fertility in mice\u2020"],"prefix":"10.1093","volume":"103","author":[{"given":"Kiyonori","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan"},{"name":"Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Endo","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan"},{"name":"Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan"},{"name":"Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Lu","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery and Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin M","family":"Matzuk","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery and Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan"},{"name":"Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan"},{"name":"Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan"},{"name":"Graduate School of Medicine, Osaka University, Suita, Osaka, Japan"},{"name":"The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,17]]},"reference":[{"key":"2020080407010211400_ref1","volume-title":"Histological and Histopathological Evaluation of the 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