Rb-Id2 Pathway in Mouse Development and Tumorigenesis

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DESCRIPTION (provided by applicant): In mammalian cells, the Retinoblastoma (Rb) tumor suppressor protein is essential to execute terminal cell cycle withdrawal, complete differentiation and secure cell survival. In the absence of Rb, mouse development is impaired and Rb-mutant embryos die at mid-gestation with severe defects in erythropoiesis and neurogenesis. The helix-loop helix protein Inhibitor of differentiation 2 (Id2) coordinates proliferation and differentiation. Id2 binds Rb and antagonizes its antiproliferative function. We have recently reported that ablation of the mouse Id2 gene rescues the phenotypic abnormalities and lethality of Rb-mutant embryos. These results have identified Id2 as a relevant target of tumor suppressor proteins, whose function must be restrained by Rb during development. The long-term goal of this work is to understand the role of Rb-Id2 complexes in proliferation, differentiation and tumorigenesis using genetically modified mouse models. We have found that Rb is essential for differentiation of the macrophage/dendritic cell lineage, a cell type required to support erythropoiesis in the fetal liver. This is an exciting novel finding that will allow us to dissect the most relevant Rb-null defect, in order to trace the molecular events directed by the Rb-Id2 pathway in erythropoiesis. We will also determine the target specificity of Id2 in cell proliferation and differentiation by discriminating Id2 and E2F functions in the absence of Rb. Finally, to establish the role of Id2 in tumorigenesis initiated by inactivation of Rb, we will use a mouse model in which mutation of Rb predisposes to pituitary cancer. These experiments will increase our understanding of the mechanisms by which Rb promotes cell cycle arrest and differentiation in normal cells and the perturbation of these mechanisms in cellular transformation.