Estrogen-dependent proteolytic cleavage of semaphorin 4D and plexin-B1 enhances semaphorin 4D-induced apoptosis during postnatal vaginal remodeling in pubescent mice
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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.
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In female rodents, the first indicator of the pubertal rise in estradiol is vaginal opening, during which increased circulating estradiol induces apoptosis in cells that form a thin sheath over the vaginal opening.
“In female rodents, the first indicator of the pubertal rise in estradiol is vaginal opening, during which increased circulating estradiol induces apoptosis in cells that form a thin sheath over the vaginal opening”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Ito et al., 2014
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Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?
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- Authors
- Ito, T., Bai, T., Tanaka, T., Yoshida, K., Ueyama, T., Miyajima, M., Negishi, T., Kawasaki, T., Takamatsu, H., Kikutani, H., Kumanogoh, A., & Yukawa, K.
- Affiliations
- Meijo University (JP)
- Wakayama Medical University (JP)
- National Institute of Genetics (JP)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Yukawa, Kazunori
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-19
- Volume
- 9
- Issue
- 5
- Pages
- e97909
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4026538
- OpenAlex
- W1996443695
- Cited by
- 12
- References
- 30
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2019: 1 · 2017: 1 · 2016: 3
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Meijo University
- Japan Society for the Promotion of Science (24590895, 19590178)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- Sema4D, Plexin-B1, estrogen signaling, apoptosis, vaginal opening, vaginal epithelium, proteolytic cleavage, imperforate vagina, hydrometrocolpos, puberty, Akt dephosphorylation, ERK dephosphorylation, ovariectomy, female genital tract development
- MeSH terms
- Analysis of Variance, Animals, Estrogens, Female, Immunohistochemistry, Nerve Tissue Proteins, Puberty, Receptors, Cell Surface, Vagina, Blotting, Western, Antigens, CD, Apoptosis, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Semaphorins, Mice, Proteolysis, Real-Time Polymerase Chain Reaction
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