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Hedgehog signaling regulates the basement membrane remodeling during folliculogenesis in the neonatal mouse ovary

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Abstract

In the mouse ovary, interactions between oocytes and somatic cells are essential for folliculogenesis and subsequent follicle development. The polyovular follicle (PF), which contains more than two oocytes in a follicle, can be induced in the neonatal mouse ovary when interactions between oocytes and somatic cells are disrupted by agents such as the potent synthetic estrogen diethylstilbestrol (DES) acting through estrogen receptor (ER) β. Hedgehog signaling is known to regulate granulosa cell proliferation, thecal cell differentiation, and follicle growth. To investigate the role of hedgehog signaling in the early folliculogenesis and in PF induction by DES, neonatal mouse ovaries were cultured with or without 10 μM cyclopamine (CPA), an inhibitor of hedgehog signaling, and grafted under the kidney capsule of adult ovariectomized host mice. The number and the incidence of PFs were significantly increased in organ-cultured ovaries post-grafting. Expression of procollagen type IV, alpha 1 (Col4a1) in organ-cultured ovaries was significantly reduced by CPA, but not by DES. The expression of two hedgehog ligands, Desert hedgehog (Dhh) and Indian hedgehog (Ihh), and a target gene, Hedgehog interacting protein (Hhip), was significantly increased by DES both in WT and ERβ KO mice. Therefore, we infer that DES can affect expression of those genes through ERα but not via suppression of hedgehog signaling. Thus, PFs are induced by DES or CPA, but the induction mechanism is different. Our results revealed an important role of hedgehog signaling in basement membrane remodeling during folliculogenesis even before thecal cell differentiation.

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Acknowledgments

We thank Professor Bruce Blumberg, Department of Developmental and Cell Biology, University of California, Irvine for his critical reading of this manuscript and Professor Pierre Chambon, University of Strasbourg, France for providing ERβKO mice.

Funding

This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant-in-Aid for Scientific Research (B) to T.I., Grant-in-Aid for Scientific Research (C) to T.S.], Yokohama City University (Grants for Support of the Promotion of Research W18005, K2109, G2314, G2401, and IR2502 to T.S).

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Authors and Affiliations

  1. Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama, 236-0027, Japan

    Karin J. Terauchi, Taisen Iguchi & Tomomi Sato

  2. Department of Biological Science and Technology, Tokyo University of Science, Tokyo, 125-8585, Japan

    Shinichi Miyagawa

Authors
  1. Karin J. Terauchi
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  2. Shinichi Miyagawa
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  3. Taisen Iguchi
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  4. Tomomi Sato
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Contributions

KJT and TS designed and performed research; KJT analyzed data; SM provided ERβ knockout mice; KJT, TI, and TS wrote the paper.

Corresponding author

Correspondence to Tomomi Sato.

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The authors declare that they have no conflict of interest.

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All animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and all experiments were approved by the Institutional Animal Care Committee of the Yokohama City University.

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Terauchi, K.J., Miyagawa, S., Iguchi, T. et al. Hedgehog signaling regulates the basement membrane remodeling during folliculogenesis in the neonatal mouse ovary. Cell Tissue Res 381, 555–567 (2020). https://doi.org/10.1007/s00441-020-03222-9

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  • DOI: https://doi.org/10.1007/s00441-020-03222-9

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