title: Uterine development and fertility are dependent on gene dosage of the nuclear receptor coregulator REA.
abstract: Although the effectiveness of nuclear hormone-receptor complexes is known to depend on coregulator partner proteins, relatively little is known about the roles of coregulators in uterine development and early stages of pregnancy and implantation. Because conventional genetic deletion of the coregulator, repressor of estrogen receptor activity (REA), was embryonic lethal, we here study REA conditional knockout mice generated by cre-loxP recombination, in which REA function was abrogated only in progesterone receptor-expressing tissues, to define the roles of REA in postembryonic stages and in a tissue-specific manner. We find that REA has gene dose-dependent activity impacting uterine development and fertility. Conditional homozygous mutant (REA(d/d)) mice developed to adulthood and showed normal ovarian function, but females were infertile with severely compromised uterine development and function characterized by cell cycle arrest, apoptosis, and altered adenogenesis (endometrial gland morphogenesis), resulting in failure of implantation and decidualization. By contrast, mice heterozygous for REA (REA(f/d)) had a very different phenotype, with estradiol treatment resulting in hyperstimulated, large uteri showing increased proliferation of luminal epithelial cells, and enhanced fluid imbibition associated with altered regulation of aquaporins. These REA(f/d) female mice showed a subfertility phenotype with reduced numbers and sizes of litters. These findings highlight that uterine development and regulation of estrogen receptor activities show a bimodal dependence on the gene dosage of REA. Optimal uterine development and functional activities require the normal gene dosage of REA, with partial or complete deletion resulting in hyperresponsiveness or underresponsiveness to hormone and subfertility or infertility, respectively.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704, USA.
authors.forename: Sunghee
authors.initials: S
authors.lastname: Park
authors.forename: Sangyeon
authors.initials: S
authors.lastname: Yoon
authors.forename: Yuechao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Seong-Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D010064:Embryo Implantation / Q000235:genetics / Q000502:physiology; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins