Estrogen-dependent proteolytic cleavage of semaphorin 4D and plexin-B1 enhances semaphorin 4D-induced apoptosis during postnatal vaginal remodeling in pubescent mice.
Around the fifth week after birth, the vaginal cavity in female mouse pups opens to the overlaying skin. This postnatal tissue remodeling of the genital tract occurs during puberty, and it largely depends upon hormonally induced apoptosis that mainly occurs in the epithelium at the lower part of the mouse vaginal cavity. Previously, we showed that most BALB/c mice lacking the class IV Semaphorin (Sema4D) develop imperforate vagina and hydrometrocolpos; therefore, we reasoned that the absence of Sema4D-induced apoptosis in vaginal epithelial cells may cause the imperforate vagina. Sema4D signals via the Plexin-B1 receptor; nevertheless detailed mechanisms mediating this hormonally triggered apoptosis are not fully documented. To investigate the estrogen-dependent control of Sema4D signaling during the apoptosis responsible for mouse vaginal opening, we examined structural and functional modulation of Sema4D, Plexin-B1, and signaling molecules by analyzing both wild-type and Sema4D-/- mice with or without ovariectomy. Both the release of soluble Sema4D and the conversion of Plexin-B1 by proteolytic processing in vaginal tissue peaked 5 weeks after birth of wild-type BALB/c mice at the time of vaginal opening. Estrogen supplementation of ovariectomized wild-type mice revealed that both the release of soluble Sema4D and the conversion of Plexin-B1 into an active form were estrogen-dependent and concordant with apoptosis. Estrogen supplementation of ovariectomized Sema4D-/- mice did not induce massive vaginal apoptosis in 5-week-old mice; therefore, Sema4D may be an essential apoptosis-inducing ligand that acts downstream of estrogen action in vaginal epithelium during this postnatal tissue remodeling. Analysis of ovariectomized mice also indicated that Sema4D contributed to estrogen-dependent dephosphorylation of Akt and ERK at the time of vaginal opening. Based on our results, we propose that apoptosis in vaginal epithelium during postnatal vaginal opening is induced by enhanced Sema4D signaling that is caused by estrogen-dependent structural changes of Sema4D and Plexin-B1.
Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Takuji
T
Ito
Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.
Tao
T
Bai
Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.
Tetsuji
T
Tanaka
Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Kenji
K
Yoshida
Department of Anatomy and Cell Biology, Wakayama Medical University, Wakayama, Japan.
Takashi
T
Ueyama
Laboratory Animal Center, Wakayama Medical University, Wakayama, Japan.
Masayasu
M
Miyajima
Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Takayuki
T
Negishi
Division of Brain Function, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima, Japan.
Takahiko
T
Kawasaki
Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Hyota
H
Takamatsu
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Hitoshi
H
Kikutani
Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Atsushi
A
Kumanogoh
Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Kazunori
K
Yukawa
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011627:Puberty / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D014621:Vagina / Q000254:growth & development*
D015703:Antigens, CD; C093224:CD100 antigen; D004967:Estrogens; D009419:Nerve Tissue Proteins; C492118:Plxnb1 protein, mouse; D011956:Receptors, Cell Surface; D039961:Semaphorins