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Hedgehog signaling plays roles in epithelial cell proliferation in neonatal mouse uterus and vagina

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Abstract

Both the uterus and vagina develop from the Müllerian duct but are quite distinct in morphology and function. To investigate factors controlling epithelial differentiation and cell proliferation in neonatal uterus and vagina, we focused on Hedgehog (HH) signaling. In neonatal mice, Sonic hh (Shh) was localized in the vaginal epithelium and Indian hh (Ihh) was slightly expressed in the uterus and vagina, whereas all Glioma-associated oncogene homolog (Gli) genes were mainly expressed in the stroma. The expression of target genes of HH signaling was high in the neonatal vagina and in the uterus, it increased with growth. Thus, in neonatal mice, Shh in the vaginal epithelium and Ihh in the uterus and vagina activated HH signaling in the stroma. Tissue recombinants showed that vaginal Shh expression was inhibited by the vaginal stroma and uterine Ihh expression was stimulated by the uterine stroma. Addition of a HH signaling inhibitor decreased epithelial cell proliferation in organ-cultured uterus and vagina and increased stromal cell proliferation in organ-cultured uterus. However, it did not affect epithelial differentiation or the expression of growth factors in organ-cultured uterus and vagina. Thus, activated HH signaling stimulates epithelial cell proliferation in neonatal uterus and vagina but inhibits stromal cell proliferation in neonatal uterus.

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Acknowledgements

The authors are grateful to Dr. Anke Lange, Biosciences, College of Life & Environmental Sciences, University of Exeter, United Kingdom and to Dr. Raphael Guzman, Department of Molecular Cell Biology and Cancer Research Laboratory of University of California at Berkeley for their critical reading of this article.

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Authors and Affiliations

  1. Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan

    Tadaaki Nakajima & Tomomi Sato

  2. The Graduate University for Advanced Studies and Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, 444-8787, Japan

    Taisen Iguchi

Authors
  1. Tadaaki Nakajima
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  2. Taisen Iguchi
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  3. Tomomi Sato
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Corresponding author

Correspondence to Tomomi Sato.

Additional information

This work was partially supported by a Grant-in-Aid for Scientific Research (B) to T.I. from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants for Strategic Research Projects at Yokohama City University (nos. K19020, K2109, G2201 and W18005 to T.S.), a Health Sciences Research Grant from the Ministry of Health, Labor and Welfare, Japan (to T.I.) and a Grant for Support of the Collaborative Study at NIBB (to T.S). T.N. is a Research Fellow of the Japan Society for the Promotion of Science.

The authors declare no conflicts of interest.

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Supplemental Table

Primers used for real-time RT-PCR and RT-PCR. (DOC 51 kb)

Supplemental Figure

Shh, Ihh, Dhh, Ptch1, Ptch2, Gli1, Gli2, and Gli3 mRNA expression levels in the vagina in oil-treated (C) or E2-treated (E2) ovariectomized mice at day 90 were analyzed by real-time RT-PCR. Data are expressed relative to mRNA expression of the oil-treated vagina at day 90; relative expression = 1.0 (*P<0.05 compared with oil-treated vagina). (JPEG 21 kb)

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Nakajima, T., Iguchi, T. & Sato, T. Hedgehog signaling plays roles in epithelial cell proliferation in neonatal mouse uterus and vagina. Cell Tissue Res 348, 239–247 (2012). https://doi.org/10.1007/s00441-012-1350-7

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  • DOI: https://doi.org/10.1007/s00441-012-1350-7

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