Rb regulates fate choice and lineage commitment in vivo

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Abstract
The tumour suppressor Rb (retinoblastoma protein) is mutated in about one-third of human tumours. It suppresses the activity of certain transcription factors and potentiates the activity of others, and has been shown to affect the differentiation of different cell lineages in vitro. Jacqueline Lees and colleagues now show that Rb plays a role in determining fate choice between bone cell and brown adipose tissue formation in vivo in mouse osteosarcoma models, acting via the bone and fat master regulators Runx2 and PPARγ The retinoblastoma tumour suppressor protein pRb can suppress the activity of certain transcription factors and potentiate the activity of others, and has been shown to affect the differentiation of different cell lineages in vitro. These authors show that the Rb gene has a role in driving bone cell formation or brown adipose tissue formation in vivo. 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.