Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

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.

Nuclear and Membrane Receptors for Sex Steroids Are Involved in the Regulation of Delta/Serrate/LAG-2 Proteins in Rodent Sertoli Cells

“…We have recently reported that testosterone increases the activity of the Notch pathway in rat and mouse Sertoli cells, upregulating the expression of Notch1 intracellular domain and the effector genes Hes1 and Hey1 [46]. In light of these data, the results of the present study suggest that enhanced Notch pathway activity following testosterone exposure may be, at least to some extent, associated with reduced expression of DLL1 or JAG1 proteins, which potentially prevents cis-inhibitory interactions within Sertoli cells.…”

Analysis of circRNA-miRNA-mRNA regulatory network of embryonic gonadal development in Mulard duck

“…In addition to the dorso-ventral axis formation pathway, NOTCH genes are also involved in signaling pathways. There was an interaction between androgen and the Notch signaling pathway in Sertoli cells ( Kamińska et al, 2020 ). Additionally, the Notch signaling pathway significantly affects the reproductive organ development of male mice ( Lupien et al, 2006 ) and may be an important pathway for the physiological regulation of Sertoli cells, with these changes potentially leading to disturbances in the response of Sertoli cells to androgens ( Kamińska et al, 2020 ); however, differences in the Notch signaling pathway were not significant in this study.…”

The peptide fraction of Bothrops jararaca snake venom induces toxicological effects on the male reproductive system after local envenomation in mice

“…C: cells untreated; C+: cells treated with sodium nitroprusside; Bj-CV: crude venom of Bothrops jararaca snake; Bj-PF: peptide fraction obtained from crude venom. Gu et al, 2022;Kamińska et al, 2020). For this reason, we used an in vitro culture model of 15P-1 Sertoli cells to study the effects of Bj-PF on mitochondrial metabolism and NO generation in this cell type of the seminiferous epithelium.…”