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Molecular and Cellular Biology, June 2004, p. 4994-5004, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4994-5004.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Muktar A. Mahajan,1 Sharmistha Das,1 Hong Zhu,1 Marjana Tomic-Canic,2 and Herbert H. Samuels1*

Departments of Pharmacology and Medicine,1 Departments of Dermatology and Microbiology, New York University School of Medicine, New York, New York 100162

Received 7 January 2004/ Returned for modification 4 February 2004/ Accepted 18 March 2004

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-{kappa}B). 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.

* Corresponding author. Mailing address: Departments of Pharmacology and Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-6279. Fax: (212) 263-7133. E-mail: herbert.samuels{at}med.nyu.edu.

Molecular and Cellular Biology, June 2004, p. 4994-5004, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4994-5004.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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