Human ERR gamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: Tissue-specific isoforms are expressed during development and in the adult

The nuclear receptor protein superfamily is a large group of transcription factors involved in many aspects of animal development, tissue differentiat ion, and homeostasis in the higher eukaryotes. A subfamily of receptors, ER R alpha and beta (estrogen receptor-related receptor alpha and beta), close ly related to the ER, were among the first orphan nuclear receptors identif ied. These receptors can bind DNA as monomers and are thought to activate t ranscription constitutively, unaffected by beta-estradiol. Studies of the e xpression patterns of ERR alpha and gene disruption experiments of ERR beta indicate that they play an important role in the development and different iation of specific tissues in the mouse. In this work we demonstrate the ex istence in humans of a third member of this subfamily of receptors, termed ERR gamma, which is highly expressed in a number of diverse fetal and adult tissues including brain, kidney, pancreas, and placenta. The ERR gamma mRN A is highly alternatively spliced at the 5'-end, giving rise to a number of tissue-specific RNA species, some of which code for protein isoforms diffe ring in the N-terminal region. Like ERR alpha and beta, ERR gamma binds as a monomer to an ERRE. A GAL4-ERR gamma fusion protein activates transcripti on in a ligand-independent manner in transfected HEK293 cells to a greater degree than either the GAL-4ERR alpha or -beta fusion proteins.