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Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP 9 in mouse Sertoli cells
Author(s) -
Kamińska A.,
Pardyak L.,
Marek S.,
Wróbel K.,
KotulaBalak M.,
Bilińska B.,
Hejmej A.
Publication year - 2020
Publication title -
andrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.947
H-Index - 43
eISSN - 2047-2927
pISSN - 2047-2919
DOI - 10.1111/andr.12691
Subject(s) - notch signaling pathway , androgen receptor , sertoli cell , signal transduction , androgen , microbiology and biotechnology , receptor , gene silencing , biology , medicine , chemistry , endocrinology , spermatogenesis , hormone , biochemistry , gene , prostate cancer , cancer
Background Notch signaling pathway is involved in contact‐dependent communication between the cells of seminiferous epithelium, and its proper activity is important for undisturbed spermatogenesis. Objectives The aim was to assess the effect of Notch pathway inhibition on the expression of nuclear ( AR ) and membrane ( ZIP 9) androgen receptors and androgen‐regulated genes, claudin‐5 and claudin‐11, in TM 4 mouse Sertoli cell line. Materials and methods DAPT (γ‐secretase inhibitor) treatment and recombination signal binding protein silencing were employed to reduce Notch signaling, whereas immobilized ligands were used to activate Notch pathway in TM 4 cells. To reveal specific effect of each androgen receptor, AR or ZIP 9 silencing was performed. Results Notch pathway inhibition increased the expression of AR and ZIP 9 mRNA and proteins ( p < 0.01; p < 0.05) in TM 4 cells, whereas incubation with Notch ligands, rDLL 1 or rJAG 1, reduced AR ( p < 0.01; p < 0.001) and ZIP 9 ( p < 0.05; p < 0.01) expressions, respectively. Testosterone enhanced the expression of both receptors ( p < 0.05; p < 0.01). Androgen‐regulated claudin‐5 and claudin‐11 ( p < 0.01; p < 0.001) and cAMP ( p < 0.001) were elevated in Notch‐inhibited cells, while activation of Notch signaling by DLL 1 or JAG 1 reduced claudin‐11 or claudin‐5 level ( p < 0.01; p < 0.001), respectively. Discussion Our findings indicate opposite effect of Notch and androgen signaling on the expression of androgen receptors in TM 4 cells. We demonstrated that AR expression is regulated by DLL 1‐mediated Notch signaling, whereas JAG 1 is involved in the regulation of ZIP 9. The expression of both claudins and cAMP production is under inhibitory influence of Notch pathway. The effects of Notch signaling on claudin‐5 and claudin‐11 expression are mediated by ZIP 9 and AR , respectively. Conclusion Notch signaling may be considered as an important pathway controlling Sertoli cell physiology, and its alterations may contribute to disturbed response of Sertoli cells to androgens.