Estrogen-dependent and -independent estrogen receptor-alpha signaling separately regulate male fertility.
Estrogen receptor-alpha (ERalpha) plays a critical role in male reproductive tract development and fertility. To determine whether estrogen-dependent and -independent ERalpha mechanisms are involved in male fertility, we examined male estrogen nonresponsive ERalpha knock-in mice. These animals have a point mutation (G525L) in the ligand-binding domain of ERalpha that significantly reduces interaction with, and response to, endogenous estrogens but does not affect growth factor activation of ligand-independent ERalpha pathways. Surprisingly, we found that ligand-independent ERalpha signaling is essential for concentrating epididymal sperm via regulation of efferent ductule fluid reabsorption. In contrast, estrogen-dependent ERalpha signaling is required for germ cell viability, most likely through support of Sertoli cell function. By treating estrogen nonresponsive ERalpha knock-in (ENERKI) mice with the ERalpha selective synthetic agonist propyl pyrazole triol, which is able to bind and activate G525L ERalpha in vivo, we discovered male fertility required neonatal estrogen-mediated ERalpha signaling. Thus, our work indicates both estrogen-dependent and -independent pathways play separable roles in male murine reproductive tract development and that the role of ERalpha in human infertility should be examined more closely.
Sinkevicius
Kerstin W
KW
The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA.
Laine
Muriel
M
Lotan
Tamara L
TL
Woloszyn
Karolina
K
Richburg
John H
JH
Greene
Geoffrey L
GL
D000818:Animals; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D055879:Gene Knock-In Techniques; D007248:Infertility, Male / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009845:Oligospermia; D010636:Phenols; D017354:Point Mutation / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D012670:Seminiferous Epithelium / Q000503:physiopathology; D012708:Sertoli Cells / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013739:Testosterone / Q000097:blood
D047628:Estrogen Receptor alpha; D004967:Estrogens; D010636:Phenols; D011720:Pyrazoles; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D013739:Testosterone