title: Epididymal C4b-binding protein is processed and degraded during transit through the duct and is not essential for fertility.
abstract: C4b-binding protein (C4BP) is known as one of the circulating complement regulators that prevents excessive activation of the host-defense complement system. We have reported previously that C4BP is expressed abundantly in the rodent epididymis, one of the male reproductive organs connecting the testis and vas deferens, where immature spermatozoa acquire their motility and fertilizing ability during their transit through the duct. Epididymal C4BP (EpC4BP) is synthesized androgen-dependently by the epithelial cells, secreted into the lumen, and bound to the outer membrane of the passing spermatozoa. In this study, we found that EpC4BP is secreted as a large oligomer, similar to the serum C4BP, but is digested during the epididymal transit and is almost lost from both the luminal fluid and the sperm surface in the vas deferens. Such a processing pattern is not known in serum C4BP, suggesting that EpC4BP and serum C4BP might have different functional mechanisms, and that there is a novel function of EpC4BP in reproduction. In addition, the disappearance of EpC4BP from the sperm surface prior to ejaculation suggests that EpC4BP works only in the epididymis and would not work in the female reproductive tract to protect spermatozoa from complement attack. Next, we generated C4BP-deficient (C4BP-/-) mice to examine the possible role of EpC4BP in reproduction. However, the C4BP-/- mice were fertile and no significant differences were observed between the C4BP-/- and wild-type mouse spermatozoa in terms of morphology, motility, and rate of the spontaneous acrosome reaction. These results suggest that EpC4BP is involved in male reproduction, but not essential for sperm maturation.
authors.affiliation: Department of Biological Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: nmayumi@bs.s.u-tokyo.ac.jp.
authors.forename: Mayumi I
authors.initials: MI
authors.lastname: Nonaka
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Zsigmond
authors.affiliation: Department of Anatomy, Kyorin University School of Medicine, Mitaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kudo
authors.affiliation: Department of Anatomy, Kyorin University School of Medicine, Mitaka, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Biomedical Engineering Center, Toin University of Yokohama, Yokohama, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Misaki Marine Biological Station, The University of Tokyo, Miura, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kawano
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Miyado
authors.affiliation: Department of Biological Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Nonaka
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, USA.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Wetsel
mesh_terms: D000177:Acrosome / Q000378:metabolism; D000818:Animals; D050716:Complement C4b-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004822:Epididymis / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005298:Fertility / Q000235:genetics; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D021381:Protein Transport; D059748:Proteolysis; D013079:Sperm Maturation / Q000235:genetics; D013081:Sperm Motility / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D050716:Complement C4b-Binding Protein
keywords: C4BP; Complement; Epididymis; Gene targeting; Processing; Reproduction; Sperm maturation