Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects.

The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb;p107 double-mutant embryos (DKOs) that develop in the absence of placental defects.

The retinoblastoma protein tumor suppressor is important for appropriate osteoblast differentiation and bone development.

Mutation of the retinoblastoma (RB) tumor suppressor gene is strongly linked to osteosarcoma formation. This observation and the documented interaction between the retinoblastoma protein (pRb) and Runx2 suggests that pRb is important in bone development. To assess this hypothesis, we used a conditional knockout strategy to generate pRb-deficient embryos that survive to birth.

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage.

Mutation of the RB-1 and p53 tumor suppressors is associated with the development of human osteosarcoma. With the goal of generating a mouse model of this disease, we used conditional and transgenic mouse strains to inactivate Rb and/or p53 specifically in osteoblast precursors. The resulting Rb;p53 double mutant (DKO) animals are viable but develop early onset osteosarcomas with complete penetrance.

E2f4 is required for normal development of the airway epithelium.

The airway epithelium is comprised of specialized cell types that play key roles in protecting the lungs from environmental insults. The cellular composition of the murine respiratory epithelium is established during development and different cell types populate specific regions along the airway. Here we show that E2f4-deficiency leads to an absence of ciliated cells from the entire airway epithelium and the epithelium of the submucosal glands in the paranasal sinuses.

Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues.

The tumor suppressor function of the retinoblastoma protein pRB is largely dependent upon its capacity to inhibit the E2F transcription factors and thereby cell proliferation. Attempts to study the interplay between pRB and the E2Fs have been hampered by the prenatal death of Rb; E2f nullizygous mice. In this study, we isolated Rb; E2f3 mutant embryonic stem cells and generated Rb(-/-); E2f3(-/-) chimeric mice, thus bypassing the lethality of the Rb(-/-); E2f3(-/-) germ line mutant mice.

Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo.

The E2F1, -2, and -3 transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor that drive expression of proliferation-associated genes. Here we use mutant mouse strains to investigate E2F3's role in vivo. We show that E2F3 is essential for embryonic viability in the pure 129/Sv background but the presence of C57BL/6 alleles yields some adult survivors.