Membrane-Localized Estrogen Receptor α Is Required for Normal Organ Development and Function

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 alpha (ER alpha) knockin mouse (C451A) that precludes palmitoylation and membrane trafficking of the steroid receptor in all organs. Homozygous knockin female mice (nuclear-only ER alpha [NOER]) show loss of rapid signaling that occurs from membrane ER alpha 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 ER alpha and resulting signal transduction to collaborate with nuclear ER alpha for normal development and function.