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Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation.

ABSTRACT: The mesenchymal cell is a multipotent stem cell with the capacity to give rise to multiple cell types such as adipocytes, osteoblasts, chondrocytes, and myocytes. However, the molecular events responsible for their lineage specification and differentiation remain obscure. Here we show that inactivation of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a member of the nuclear receptor superfamily, in mesenchymal progenitors favors osteoblast and myoblast development while simultaneously impairing adipogenic and chondrogenic programs. During mouse embryogenesis, COUP-TFII protein is highly detected in the mesenchymal compartment and is involved in mesoderm tissue formation. Ablation of COUP-TFII in mice led to higher bone density, increased muscle mass, and suppression of cartilage and fat formation. We further demonstrate that COUP-TFII directs the plasticity of mesenchymal precursors primarily through the combined modulation of Wnt signaling, Runx2 activity, as well as PPAR? and Sox9 expression. Together, our results provide insight into the mechanisms whereby a single nuclear receptor can fine-tune the lineage-specific differentiation of a progenitor cell.

SUBMITTER: Xie X

PROVIDER: S-EPMC3169151 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation.

Xie Xin X Qin Jun J Lin Sue-Hwa SH Tsai Sophia Y SY Tsai Ming-Jer MJ

Proceedings of the National Academy of Sciences of the United States of America 20110822 36

The mesenchymal cell is a multipotent stem cell with the capacity to give rise to multiple cell types such as adipocytes, osteoblasts, chondrocytes, and myocytes. However, the molecular events responsible for their lineage specification and differentiation remain obscure. Here we show that inactivation of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a member of the nuclear receptor superfamily, in mesenchymal progenitors favors osteoblast and myoblast development whil ...[more]

PMID: 21873211

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Project description:BackgroundUcp3 is an integral protein of the inner mitochondrial membrane with a role in lipid metabolism preventing deleterious effects of fatty acids in states of high lipid oxidation. Ucp3 is expressed in brown adipose tissue and skeletal muscle and controlled by a transcription factor complex including PPARalpha, MyoD and the histone acetyltransferase p300. Several studies have demonstrated interaction of these factors with chicken ovalbumin upstream promoter transcription factor II (Coup-TFII). This nuclear receptor is involved in organogenesis and other developmental processes including skeletal muscle development, but also co-regulates a number of metabolic genes. In this study we in silico analyzed the upstream region of Ucp3 of the Djungarian hamster Phodopus sungorus and identified several putative response elements for Coup-TFII. We therefore investigated whether Coup-TFII is a further player in the transcriptional control of the Ucp3 gene in rodents.ResultsBy quantitative PCR we demonstrated a positive correlation of Coup-TFII and Ucp3 mRNA expression in skeletal muscle and brown adipose tissue in response to food deprivation and cold exposure, respectively. In reporter gene assays Coup-TFII enhanced transactivation of the Ucp3 promoter conveyed by MyoD, PPARalpha, RXRalpha and/or p300. Using deletions and mutated constructs, we identified a Coup-TFII enhancer element 816-840 bp upstream of the transcriptional start site. Binding of Coup-TFII to this upstream enhancer was confirmed in electrophoretic mobility shift and supershift assays.ConclusionTranscriptional regulation of the Coup-TFII gene in response to starvation and cold exposure seems to be the regulatory mechanism of Ucp3 mRNA expression in brown adipose and skeletal muscle tissue determining the final appropriate rate of transcript synthesis. These findings add a crucial component to the complex transcriptional machinery controlling expression of Ucp3. Given the substantial evidence for a function of Ucp3 in lipid metabolism, Coup-TFII may not only be a negative regulator of glucose responsive genes but also transactivate genes involved in lipid metabolism.

Dataset Information

Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation.

Publications

Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation.

Similar Datasets

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