TY - JOUR
T1 - The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation
AU - Lee, Mary P.
AU - Tanabe, Osamu
AU - Shi, Lihong
AU - Jearawiriyapaisarn, Natee
AU - Lucas, Daniel
AU - Engel, James Douglas
N1 - Funding Information:
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (grant F32DK108493) (M.P.L.) and National Heart, Lung, and Blood Institute (grant U01HL117658) (J.D.E.). N.J. received support as an Excellence in Hemoglobinopathies Research Award Translational Research Scholar (grant U01HL117658).
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/12/7
Y1 - 2017/12/7
N2 - The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress «- and g-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr41/2 mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Surprisingly, we found that homozygous Tr4 null mutant mice expired early during embryogenesis, around embryonic day 7.0, and well before erythropoiesis commences. We further found that Tr41/2 erythroid cells failed to fully differentiate and exhibited diminished proliferative capacity. Analysis of Tr41/2 mutant erythroid cells revealed that reduced TR4 abundance resulted in decreased expression of genes required for heme biosynthesis and erythroid differentiation (Alad and Alas2), but led to significantly increased expression of the proliferation inhibitory factor, cyclin dependent kinase inhibitor (Cdkn1c). These studies support a vital role for TR4 in promoting erythroid maturation and proliferation, and demonstrate that TR4 and TR2 execute distinct, individual functions during embryogenesis and erythroid differentiation.
AB - The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress «- and g-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr41/2 mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Surprisingly, we found that homozygous Tr4 null mutant mice expired early during embryogenesis, around embryonic day 7.0, and well before erythropoiesis commences. We further found that Tr41/2 erythroid cells failed to fully differentiate and exhibited diminished proliferative capacity. Analysis of Tr41/2 mutant erythroid cells revealed that reduced TR4 abundance resulted in decreased expression of genes required for heme biosynthesis and erythroid differentiation (Alad and Alas2), but led to significantly increased expression of the proliferation inhibitory factor, cyclin dependent kinase inhibitor (Cdkn1c). These studies support a vital role for TR4 in promoting erythroid maturation and proliferation, and demonstrate that TR4 and TR2 execute distinct, individual functions during embryogenesis and erythroid differentiation.
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U2 - 10.1182/blood-2017-05-783159
DO - 10.1182/blood-2017-05-783159
M3 - Article
C2 - 29018082
AN - SCOPUS:85037647734
VL - 130
SP - 2537
EP - 2547
JO - Blood
JF - Blood
SN - 0006-4971
IS - 23
ER -