title: Roles of testicular orphan nuclear receptors 2 and 4 in early embryonic development and embryonic stem cells.
abstract: 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.
authors.affiliation: Department of Pathology, The Cancer Center, George Whipple Lab for Cancer Research, University of Rochester, Rochester, New York 14642, USA.
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Hong-Yo
authors.initials: HY
authors.lastname: Kang
authors.forename: Meng-Yin
authors.initials: MY
authors.lastname: Tsai
authors.forename: Ning-Chun
authors.initials: NC
authors.lastname: Liu
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Ku
authors.forename: Ko-En
authors.initials: KE
authors.lastname: Huang
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D001755:Blastocyst / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D010012:Osteogenesis / Q000235:genetics; D011247:Pregnancy; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013737:Testis / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C539823:Nr2c1 protein, mouse; C490514:Nr2c2 protein, mouse; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014212:Tretinoin