Abstract
Our recent study demonstrated altered expression of Notch ligands, receptors, and effector genes in testes of pubertal rats following reduced androgen production or signaling. Herein we aimed to explore the role of nuclear androgen receptor (AR) and membrane androgen receptor (Zrt- and Irt-like protein 9; ZIP9) in the regulation of Notch pathway activation in rodent Sertoli cells. Experiments were performed using TM4 and 15P-1 Sertoli cell lines and rat primary Sertoli cells (PSC). We found that testosterone (10−8 M–10−6 M) increased the expression of Notch1 receptor, its active form Notch1 intracellular domain (N1ICD) (p < 0.05, p < 0.01, p < 0.001), and the effector genes Hey1 (p < 0.05, p < 0.01, p < 0.001) and Hes1 (p < 0.05, p < 0.001) in Sertoli cells. Knockdown of AR or ZIP9 as well as antiandrogen exposure experiments revealed that (i) action of androgens via both AR and ZIP9 controls Notch1/N1ICD expression and transcriptional activity of recombination signal binding protein (RBP-J), (ii) AR-dependent signaling regulates Hey1 expression, (iii) ZIP9-dependent pathway regulates Hes1 expression. Our findings indicate a crosstalk between androgen and Notch signaling in Sertoli cells and point to cooperation of classical and non-classical androgen signaling pathways in controlling Sertoli cell function.
Highlights
Mammalian testis sperm production is a process supported and controlled by somatic cells of seminiferous epithelium, Sertoli cells
Using RNAi technique to reduce the expression of androgen receptors, we provided evidence that the effects of Notch signaling on claudin-5 and claudin-11 are dependent on the activation of ZIP9 or AR, respectively [9]
Sci. 2020, 21, 8275 deeper insight in androgen-Notch crosstalk in mammalian testis and reveal the mechanisms involved in this interaction, we aimed to explore the role of nuclear and membrane androgen receptors in the regulatioInnt
Summary
Mammalian testis sperm production is a process supported and controlled by somatic cells of seminiferous epithelium, Sertoli cells. These cells are considered to be key mediators of androgen action in the control of spermatogenesis. Binding of testosterone (major testicular androgen produced by interstitial tissue of the testis) to the AR triggers classical signaling pathway, inducing nuclear localization, dimerization, and interaction of hormone-receptor complex with androgen response element, a DNA sequence located in the regulatory region of androgen regulated genes [4]. It is well established that in adult males AR signaling in Sertoli cells is required for Sertoli cell maturation, the maintenance of the blood-testis barrier, Sertoli cell-spermatid adhesion, completion of meiosis and spermiation [6]
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