title: Membrane-localized estrogen receptor α is required for normal organ development and function.
abstract: Steroid receptors are found in discrete cellular locations, but it is unknown whether extranuclear pools are necessary for normal organ development. To assess this, we developed a point mutant estrogen receptor α (ERα) knockin mouse (C451A) that precludes palmitoylation and membrane trafficking of the steroid receptor in all organs. Homozygous knockin female mice (nuclear-only ERα [NOER]) show loss of rapid signaling that occurs from membrane ERα in wild-type mice. Multiple developmental abnormalities were found, including infertility, relatively hypoplastic uteri, abnormal ovaries, stunted mammary gland ductal development, and abnormal pituitary hormone regulation in NOER mice. These abnormalities were rescued in heterozygous NOER mice that were comparable to wild-type mice. mRNAs implicated in organ development were often poorly stimulated by estrogen only in homozygous NOER mice. We conclude that many organs require membrane ERα and resulting signal transduction to collaborate with nuclear ERα for normal development and function.
authors.affiliation: Division of Endocrinology, Department of Medicine, University of California, Irvine, Irvine, CA 92717, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Pedram
authors.affiliation: Department of Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, USA.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Razandi
authors.affiliation: Department of Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Department of Medicine, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hammes
authors.affiliation: Division of Endocrinology, Department of Medicine, University of California, Irvine, Irvine, CA 92717, USA; Department of Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, USA. Electronic address: ellis.levin@va.gov.
authors.forename: Ellis R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000215:Acylation; D000818:Animals; D002462:Cell Membrane / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D054878:Lipoylation; D008297:Male; D008321:Mammary Glands, Animal / Q000196:embryology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D038081:Organogenesis; D010053:Ovary / Q000196:embryology*; D010060:Ovulation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger