The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

摘要

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-κB). 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.