title: SEPT12-NDC1 Complexes Are Required for Mammalian Spermiogenesis.
abstract: Male factor infertility accounts for approximately 50 percent of infertile couples. The male factor-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile sperm, immature sperm, abnormally structured sperm, and sperm with nuclear damage. Our knockout and knock-in mice models demonstrated that SEPTIN12 (SEPT12) is vital for the formation of sperm morphological characteristics during spermiogenesis. In the clinical aspect, mutated SEPT12 in men results in oligozoospermia or teratozoospermia or both. Sperm with mutated SEPT12 revealed abnormal head and tail structures, decreased chromosomal condensation, and nuclear damage. Furthermore, several nuclear or nuclear membrane-related proteins have been identified as SEPT12 interactors through the yeast 2-hybrid system, including NDC1 transmembrane nucleoporin (NDC1). NDC1 is a major nuclear pore protein, and is critical for nuclear pore complex assembly and nuclear morphology maintenance in mammalian cells. Mutated NDC1 cause gametogenesis defects and skeletal malformations in mice, which were detected spontaneously in the A/J strain. In this study, we characterized the functional effects of SEPT12-NDC1 complexes during mammalian spermiogenesis. In mature human spermatozoa, SEPT12 and NDC1 are majorly colocalized in the centrosome regions; however, NDC1 is only slightly co-expressed with SEPT12 at the annulus of the sperm tail. In addition, SEPT12 interacts with NDC1 in the male germ cell line through coimmunoprecipitation. During murine spermiogenesis, we observed that NDC1 was located at the nuclear membrane of spermatids and at the necks of mature spermatozoa. In male germ cell lines, NDC1 overexpression restricted the localization of SEPT12 to the nucleus and repressed the filament formation of SEPT12. In mice sperm with mutated SEPT12, NDC1 dispersed around the manchette region of the sperm head and annulus, compared with concentrating at the sperm neck of wild-type sperm. These results indicate that SEPT12-NDC1 complexes are involved in mammalian spermiogenesis.
authors.affiliation: Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 106, Taiwan. Joseph@cgh.org.tw.|School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan. Joseph@cgh.org.tw.|Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taoyuan Country 320, Taiwan. Joseph@cgh.org.tw.
authors.forename: Tsung-Hsuan
authors.initials: TH
authors.lastname: Lai
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan. l43219713@hotmail.com.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Fu Jen Catholic University, New Taipei City 242, Taiwan. vic0009@yahoo.com.tw.
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Bone and Joint Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan. mfchen0@gmail.com.
authors.forename: Mei-Feng
authors.initials: MF
authors.lastname: Chen
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan. 078575@mail.fju.edu.tw.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan. tmtonychen@webmail.nkmu.edu.tw.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan. 133838@mail.fju.edu.tw.
authors.forename: Yi-No
authors.initials: YN
authors.lastname: Wu
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan. 053824@mail.fju.edu.tw.
authors.forename: Han-Sun
authors.initials: HS
authors.lastname: Chiang
authors.affiliation: Department of Obstetrics & Gynecology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. paolink@mail.ncku.edu.tw.
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan. 084952@mail.fju.edu.tw.
authors.forename: Ying-Hung
authors.initials: YH
authors.lastname: Lin
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000032:analysis / Q000378:metabolism*; D009698:Nucleoproteins / Q000032:analysis / Q000378:metabolism*; D058112:Septins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013091:Spermatogenesis; D013094:Spermatozoa / Q000166:cytology* / Q000378:metabolism
chemical_list: C510249:NDC1 protein, human; C000617215:NDC1 protein, mouse; D028861:Nuclear Pore Complex Proteins; D009698:Nucleoproteins; C555146:SEPT12 protein, mouse; C502729:SEPTIN12 protein, human; D058112:Septins
keywords: NDC1; SEPT12; male infertility