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Roles of Testicular Orphan Nuclear Receptors 2 and 4 in Early Embryonic Development and Embryonic Stem Cells

Departments of Pathology, Urology, and Radiation Oncology (C.-R.S., H.-Y.K., M.-Y.T., N.-C.L., K.-E.H., C.C.), The Cancer Center, George Whipple Lab for Cancer Research, University of Rochester, Rochester, New York 14642; Department of Laboratory Medicine and Biotechnology (C.-R.S.), Tzu Chi University, Hualien 97004, Taiwan; The Center for Menopause and Reproductive Medicine Research (C.-R.S., H.-Y.K., M.-Y.T., P.-Y.K., K.-E.H., C.C.), Chang Gung University/Memorial Hospital, and Graduate Institute of Clinical Medicine (H.-Y.K., M.-Y.T.), Kaohsiung Division, Chang Gung University, Kaohsiung 833, Taiwan

Address all correspondence and requests for reprints to: Chawnshang Chang, Departments of Pathology, Urology, and Radiation Oncology, The Cancer Center, George Whipple Lab for Cancer Research, University of Rochester, Rochester, New York 14642. E-mail: chang{at}urmc.rochester.edu; or Ko-En Huang, The Center for Menopause and Reproductive Medicine Research, Chang Gung University/Memorial Hospital, Kaohsiung 833, Taiwan. E-mail: khuang{at}adm.cgmh.org.tw.

The testicular orphan nuclear receptors (TRs) 2 and 4 act as either transcriptional activators or regulatory proteins of other nuclear receptor superfamily members. With no identified cognate ligands, their physiological roles remain unclear. Here we showed the phenotypes of TR2^–/–:TR4^–/– mutant embryos, which reveal that the loss of TR2 and TR4 causes early embryonic lethality and increased cell death. We also found that TR2 and TR4 are expressed in blastocysts and embryonic stem (ES) cells, and can act as transcriptional activators in ES cells. The results on further investigating the roles of TR2 and TR4 in ES cells showed that TR2 and TR4 were differentially expressed when ES cells were induced into different specialized cell types, and their expression is regulated by retinoic acid. Knocking down TR2 and TR4 mRNAs decreased the expression of Oct-3/4 and Nanog genes. Mechanism dissection suggests that TR2 and TR4 may affect the Oct-3/4 gene by binding to a direct repeat-1 element located in its promoter region, which is influenced by retinoic acid. Together, our findings highlight possible roles for TR2 and TR4 in early embryonic development by regulating key genes involved in stem cell self-renewal, commitment, and differentiation.