title: The nuclear hormone receptor coactivator NRC is a pleiotropic modulator affecting growth, development, apoptosis, reproduction, and wound repair.
abstract: Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-kappaB). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC(+/-) mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC(-/-) embryos are always smaller than NRC(+/+) embryos, and NRC(-/-) embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC(-/-) MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC(+/-) mice exhibit no apparent phenotype prompted us to develop 129S6 NRC(+/-) mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC(+/-) females, 20% of 129S6 NRC(+/-) females are infertile while 80% are hypofertile. The 129S6 NRC(+/-) males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC(+/-) mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC(+/-) and 129S6 NRC(+/-) mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.
authors.affiliation: Department of Pharmacology and Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
authors.forename: Muktar A
authors.initials: MA
authors.lastname: Mahajan
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Das
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Marjana
authors.initials: M
authors.lastname: Tomic-Canic
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Samuels
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005804:Genes, Lethal; D006579:Heterozygote; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice / Q000196:embryology / Q000254:growth & development / Q000502:physiology*; D056918:Nuclear Receptor Coactivators; D010641:Phenotype; D012098:Reproduction / Q000502:physiology*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators