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Title: The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation
Authors: Mary P. Lee
Osamu Tanabe
Lihong Shi
Natee Jearawiriyapaisarn
Daniel Lucas
James Douglas Engel
University of Michigan Medical School
Tohoku University
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 7-Dec-2017
Citation: Blood. Vol.130, No.23 (2017), 2537-2547
Abstract: © 2017 by The American Society of Hematology. 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.
ISSN: 15280020
Appears in Collections:Scopus 2016-2017

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