E2F3 and embryonic development

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DESCRIPTION (provided by applicant): The retinoblastoma (Rb) gene was the first tumor suppressor identified in humans some twenty years ago. Studies using tissue culture and in vivo mouse models have led to the identification of the E2F transcription factor family as an important effector of Rb function impacting cell proliferation, apoptosis and differentiation. Gene disruption approaches in mice have provided important clues to our understanding of the Rb/E2F pathway during development and cancer. Our recent work demonstrated that the extraembryonic function of Rb is essential for fetal development and viability, and suggested that many of the defects in Rb knockout embryos are secondary to a deficiency of Rb in extraembryonic lineages. Among E2F family members, E2F3 has emerged as a key Rb-regulated activity that controls the proliferation of normal and tumor cells. Consistent with an important function of Rb in extraembryonic tissues, inactivation of E2F3 in mice also leads to a disruption of placental development and embryonic death by E13.5. These placental abnormalities appear to be responsible for the lethality of E2F3-/- embryos because our studies show that mutant embryos supplied with normal placentas can be carried to term. While little is know about the signaling cascades in extraembryonic lineages that regulate E2F3 and trophoblast proliferation, tissue culture studies carried out in our laboratory now link the CSF1 signaling pathway to the control of E2F3 expression and spongiotrophoblast proliferation. An analysis will therefore be undertaken to determine the exact nature of these placental defects; both the causes as well as the consequences to the rest of the developing embryo will be investigated. The overarching hypothesis is that the extraembryonic function of E2F3 in spongiotrophoblasts and giant trophoblasts is essential for embryonic development and fetal viability. Together, these studies will address cause and consequence effects of E2F3 function in vivo. In doing so, we expect to attain a precise understanding of the cell autonomous and non-autonomous functions of E2F3, and to develop systems to molecularly dissect the molecular mechanism of E2F3 action. Considering that cancer in many regards can be thought to represent a developmental disorder, the results obtained from these studies, will directly impact on how we think E2F3 and Rb act during tumor progression.