Abstract
Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma1. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (pRb). The best known is pRb’s ability to promote cell-cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell-cycle regulators1. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers2. Depending on the differentiation factor and cellular context, pRb can either suppress or promote their transcriptional activity. For example, pRb binds to Runx2 and potentiates its ability to promote osteogenic differentiation in vitro3. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor γ subunit (PPAR-γ), the master activator of adipogenesis4,5. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRb might play a role in the choice between these two fates. However, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.
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Acknowledgements
We thank T. Jacks, C. Tabin and A. McMahon for providing key mutant mouse strains, K. Lane for pCW22, M. Hemann for the Rb shRNA, the University of Iowa Gene Transfer Vector Core for the adenoviral Cre and GFP vectors, and G. Karsenty for p6OSE2-Luc and control p4Luc. We also thank members of the Lees laboratory, S. Mukherjee and M. Hemann for input during this study. This work was supported by an National Cancer Institute/National Institutes of Health grant to J.A.L., who is a Ludwig Scholar at MIT.
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E.C. conducted all the experiments with assistance from J.A.Q.-E. in the Rb re-introduction study, P.S.D. and S.D.B. in the generation and analysis of compound mutant mouse strains and S.N. for the LSL-LacZ;Prx1-Cre embryo analysis. E.C. and J.A.L. were responsible for conceiving this study, interpreting the data and manuscript preparation.
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Calo, E., Quintero-Estades, J., Danielian, P. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010). https://doi.org/10.1038/nature09264
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DOI: https://doi.org/10.1038/nature09264
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