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

Abstract

Delta/Serrate/LAG-2 (DSL) proteins, which serve as ligands for Notch receptors, mediate direct cell–cell interactions involved in the determination of cell fate and functioning. The present study aimed to explore the role of androgens and estrogens, and their receptors in the regulation of DSL proteins in Sertoli cells. To this end, primary rat Sertoli cells and TM4 Sertoli cell line were treated with either testosterone or 17β-estradiol and antagonists of their receptors. To confirm the role of particular receptors, knockdown experiments were performed. mRNA and protein expressions of Jagged1 (JAG1), Delta-like1 (DLL1), and Delta-like4 (DLL4) were analyzed using RT-qPCR, Western blot, and immunofluorescence. Testosterone caused downregulation of JAG1 and DLL1 expression, acting through membrane androgen receptor ZRT- and Irt-like protein 9 (ZIP9) or nuclear androgen receptor (AR), respectively. DLL4 was stimulated by testosterone in the manner independent of AR and ZIP9 in Sertoli cells. The expression of all studied DSL proteins was upregulated by 17β-estradiol. Estrogen action on JAG1 and DLL1 was mediated chiefly via estrogen receptor α (ERα), while DLL4 was controlled via estrogen receptor β (ERβ) and membrane G-protein-coupled estrogen receptor (GPER). To summarize, the co-operation of nuclear and membrane receptors for sex steroids controls DSL proteins in Sertoli cells, contributing to balanced Notch signaling activity in seminiferous epithelium.

ZIP9 mediates the effects of DHT on learning, memory and hippocampal synaptic plasticity of male Tfm and APP/PS1 mice

“…The ZIP9 has been described as a membrane androgen receptor ( 19 , 20 , 26 , 28 , 46 , 48 , 73 – 75 ). Thomas et al.…”

“…The ZIP9 has been described as a membrane androgen receptor (19,20,26,28,46,48,(73)(74)(75). Thomas et al (24) found ZIP9 in the perinuclear and plasma membrane of MDA-MB-468 cells, while some studies also detected it in the reverse Golgi network (76).…”

“…Recent studies have found that ZIP9 can mediate biological effects of androgens in a variety of cell types. Some of these effects include proliferation of human and mouse melanoma cells ( 21 ), migration of human prostate ( 22 ) and bladder ( 23 ) cancer cells, apoptosis of human breast cancer and prostate cancer cells ( 20 , 24 , 25 ), and the expression of tight junction proteins in mouse ( 26 ) and rat ( 27 ) Sertoli cells. In a previous study it was found that androgens induced the interaction between ZIP9 and Gnα11, which affected the expression of postsynaptic density protein 95 (PSD95) in mouse hippocampal neuron HT22 cells ( 28 ).…”

Androgens, brain and androgen deprivation therapy in paraphilic disorders: A narrative review

“…First, that the classic AR is anchored to the plasma membrane; second, that a still unknown AR exists; and third, that mAR is a splice variant of the classic AR (Garza‐Contreras et al, 2017). In Sertoli cells, the membrane androgen receptor ZRT‐ and Irt‐like protein 9 (ZIP9) have been discovered (Lustofin et al, 2022). AR45, a 45 KDa mAR, a variant of the mAR is localized to lipid rafts in the plasma membrane of the neurons (Fadeyibi et al, 2022).…”

“…These different ARs allow to differentiate genomic and nongenomic androgen actions respectively. Both, nuclear and membrane receptors are expressed in the same cell (Lustofin et al, 2022).…”