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Notch signaling-mediated cell-to-cell interaction is dependent on E-cadherin adhesion in adult rat anterior pituitary

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Abstract

The rat anterior pituitary is composed of hormone-producing cells, non–hormone-producing cells (referred to as folliculostellate cells) and marginal layer cells. In the adult rat, progenitor cells of hormone-producing cells have recently been reported to be maintained within this non–hormone-producing cell population. In tissue, non–hormone-producing cells construct homophilic cell aggregates by the differential expression of the cell adhesion molecule E-cadherin. We have previously shown that Notch signaling, a known regulator of progenitor cells in a number of organs, is activated in the cell aggregates. We now investigate the relationship between Notch signaling and E-cadherin–mediated cell adhesion in the pituitary gland. Immunohistochemically, Notch signaling receptor Notch2 and the ligand Jagged1 were localized within E-cadherin–positive cells in the marginal cell layer and in the main part of the anterior lobe, whereas Notch1 was localized in E-cadherin–positive and -negative cells. Activation of Notch signaling within E-cadherin–positive cells was confirmed by immunostaining of the Notch target HES1. Notch2 and Jagged1 were always co-localized within the same cells suggesting that homologous cells have reciprocal effects in activating Notch signaling. When the E-cadherin function was inhibited by exposure to a monoclonal antibody (DECMA-1) in primary monolayer cell culture, the percentage of HES1-positive cells among Notch2-positive cells was less than half that of the control. The present results suggest that E-cadherin–mediated cell attachment is necessary for the activation of Notch signaling in the anterior pituitary gland but not for the expression of the Notch2 molecule.

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Acknowledgments

We thank Drs. Takehiro Tsukada and Ken Fujiwara for their superb guidance and experimental support. We also thank David Kipler, ELS of Supernatant Communications, for revising the language of the manuscript. This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan to M.K. (25460275), by promotional funds for the Keirin Race of the Japan Keirin Association and by a JMU Graduate Student Start-up Award to K.B.

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Authors and Affiliations

  1. Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan

    Khongorzul Batchuluun, Morio Azuma, Takashi Yashiro & Motoshi Kikuchi

  2. Laboratory of Natural History, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan

    Motoshi Kikuchi

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  1. Khongorzul Batchuluun
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  2. Morio Azuma
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  3. Takashi Yashiro
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  4. Motoshi Kikuchi
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Correspondence to Motoshi Kikuchi.

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Fig. S1

Immunohistochemistry of Notch1, Notch2, and Jagged1 in rat control tissue. Notch1 and Notch2 are known to be stably expressed in cartilage hair follicle (Pan et al. 2004; Powell et al. 1998) and Jagged1 is expressed in intestinal crypt (Sander and Powell 2004). Using abdominal skin and intestinal crypt from male Wistar rats as positive controls, we tested the validity of immunohistochemistry for Notch1, Notch2, and Jagged1. Sections were prepared and immunostained by the same method used for pituitary gland. Notch1 (a) and Notch2 (b) were detected in part of hair follicle. Jagged1 (c) was expressed in the epithelial cells of the intestinal crypt. Bars 100 μm. (PDF 106 kb)

Fig. S2

Double-staining by immunohistochemistry for Notch1 (a, d) and lectin histochemistry for endothelial cells (b, e) in frontal cryosections of rat pituitary. a-c Images from the area near the marginal layer surrounding the residual lumen of Rathke’s pouch (RC Rathke’s cleft). d-f Images from the main part of the anterior lobe. c Merged image of a, b. f Merged image of d, e (AL anterior lobe, IL intermediate lobe, PL posterior lobe). Bars 100 μm (a-c), 10 μm (d-f). For double-immunostaining, sections were blocked with 2% normal goat serum for 1 h at 30 °C and incubated in phosphate-buffered saline (PBS) with rabbit anti-human Notch1 monoclonal antibody (Cell Signaling Technology, Danvers, Mass., USA) at a dilution of 1:200 overnight at room temperature. After being washed with PBS, sections were incubated in PBS with Alexa-Fluor-568-labeled anti-rabbit IgG (Thermo Fisher Scientific, Waltham, Mass., USA) for 30 min at 30 °C. Following immunohistochemistry, lectin histochemistry was performed by using Alexa-Fluor-488-labeled isolectin B4 (Thermo Fisher Scientific), a marker of endothelial cells. Merged images (c, f) show that some Notch1 was expressed in endothelial cells in the main part of the anterior pituitary gland. (PDF 215 kb)

Fig. S3

Double-staining by immunohistochemistry for HES1 (a, d) and lectin histochemistry for endothelial cells (b, e) in frontal cryosections of rat pituitary. a-c Images from the area near the marginal layer surrounding the residual lumen of Rathke’s pouch (RC Rathke’s cleft). d-f Images from the main part of the anterior lobe. c Merged image of a, b. f Merged image of d, e (AL anterior lobe, IL intermediate lobe, PL posterior lobe). Bars 100 μm (a-c), 10 μm (d-f). Sections were heat-retrieved with an Immunosaver (Nisshin EM, Tokyo, Japan) for 10 min at 90 °C and were blocked with 2% normal goat serum for 1 h at 30 °C. They were then incubated overnight at room temperature in PBS with rabbit anti-human HES1 monoclonal antibody (Cell Signaling Technology, Danvers, Mass., USA) at a dilution of 1:500, washed with PBS, and then incubated in PBS with Alexa-Fluor-568-labeled anti-rabbit IgG (Thermo Fisher Scientific, Waltham, Mass., USA) for 30 min at 30 °C. Following immunohistochemistry, lectin histochemistry was performed by using Alexa-Fluor-488-labeled isolectin B4 (Thermo Fisher Scientific), a marker of endothelial cells. Merged images (c, f) show that some HES1 was expressed in endothelial cells in the main part of the anterior pituitary gland. (PDF 361 kb)

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Batchuluun, K., Azuma, M., Yashiro, T. et al. Notch signaling-mediated cell-to-cell interaction is dependent on E-cadherin adhesion in adult rat anterior pituitary. Cell Tissue Res 368, 125–133 (2017). https://doi.org/10.1007/s00441-016-2540-5

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  • DOI: https://doi.org/10.1007/s00441-016-2540-5

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