title: Semaphorin 4D induces vaginal epithelial cell apoptosis to control mouse postnatal vaginal tissue remodeling.
abstract: The opening of the mouse vaginal cavity to the skin is a postnatal tissue remodeling process that occurs at approximately five weeks of age for the completion of female genital tract maturation at puberty. The tissue remodeling process is primarily composed of a hormonally triggered apoptotic process predominantly occurring in the epithelium of the distal section of the vaginal cavity. However, the detailed mechanism underlying the apoptotic induction remains to be elucidated. In the present study, it was observed that the majority of BALB/c mice lacking the class 4 semaphorin, semaphorin 4D (Sema4D), developed imperforate vagina and hydrometrocolpos resulting in a perpetually unopened vaginal cavity regardless of a normal estrogen level comparable with that in wild‑type (WT) mice. Administration of β‑estradiol to infant Sema4D‑deficient (Sema4D‑/‑) mice did not induce precocious vaginal opening, which was observed in WT mice subjected to the same β‑estradiol administration, excluding the possibility that the closed vaginal phenotype was due to insufficient estrogen secretion at the time of vaginal opening. In order to assess the role of Sema4D in the postnatal vaginal tissue remodeling process, the expression of Sema4D and its receptor, plexin‑B1, was examined as well as the level of apoptosis in the vaginal epithelia of five‑week‑old WT and Sema4D‑/‑ mice. Immunohistochemical analyses confirmed the localization of Sema4D and plexin‑B1 in the mouse vaginal epithelia. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry detecting activated caspase‑3 revealed significantly fewer apoptotic cells in situ in the vaginal mucosa of five‑week‑old Sema4D‑/‑ mice compared with WT mice. The addition of recombinant Sema4D to Sema4D‑/‑ vaginal epithelial cells in culture significantly enhanced apoptosis of the vaginal epithelial cells, demonstrating the apoptosis‑inducing activity of Sema4D. The experimental reduction of plexin‑B1 expression in vaginal epithelial cells demonstrated the integral role of plexin‑B1 in Sema4D‑induced apoptotic cell death. These results suggest a non‑redundant role of Sema4D in the postnatal tissue remodeling process in five‑week‑old BALB/c mice, which involves the induction of vaginal epithelial cell apoptosis through Sema4D binding to plexin‑B1.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468‑8503, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama 641‑8509, Japan.
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama 641‑8509, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468‑8503, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Anatomy, Wakayama Medical University, Wakayama 641‑8509, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Institute for Animal Experimentation, Wakayama Medical University, Wakayama 641‑8509, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468‑8503, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.affiliation: Division of Brain Function, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima 411‑8540, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kawasaki
authors.affiliation: Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.affiliation: Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468‑8503, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014621:Vagina / Q000166:cytology / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C492118:Plxnb1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D039961:Semaphorins; D004958:Estradiol; D053148:Caspase 3