Roles of testicular orphan nuclear receptors 2 and 4 in early embryonic development and embryonic stem cells.
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.
Shyr
Chih-Rong
CR
Department of Pathology, The Cancer Center, George Whipple Lab for Cancer Research, University of Rochester, Rochester, New York 14642, USA.
Kang
Hong-Yo
HY
Tsai
Meng-Yin
MY
Liu
Ning-Chun
NC
Ku
Pei-Yu
PY
Huang
Ko-En
KE
Chang
Chawnshang
C
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
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