E2F3 and embryonic development

描述(申请人提供)：视网膜母细胞瘤(RB)基因是大约20年前在人类中发现的第一个肿瘤抑制基因。通过组织培养和体内小鼠模型的研究，已经确定E2F转录因子家族是影响细胞增殖、凋亡和分化的Rb功能的重要效应者。小鼠的基因破坏方法为我们理解Rb/E2F途径在发育和癌症过程中的作用提供了重要线索。我们最近的工作表明，Rb的胚外功能对胎儿的发育和存活是必不可少的，并提示Rb基因敲除胚胎中的许多缺陷是继发于胚外血统中Rb的缺陷。在E2F家族成员中，E2F3已成为RB调节的关键活性，控制正常细胞和肿瘤细胞的增殖。与Rb在胚胎外组织中的重要功能一致，E2F3在小鼠中的失活也会导致E13.5导致胎盘发育中断和胚胎死亡。这些胎盘异常似乎是E2F3-/-胚胎致死的原因，因为我们的研究表明，提供正常胎盘的突变胚胎可以移植到足月。虽然对胚外细胞系中调控E2F3和滋养层细胞增殖的信号通路知之甚少，但我们实验室开展的组织培养研究现已将CSF1信号通路与调控E2F3表达和海绵滋养层细胞增殖联系在一起。因此，将进行分析以确定这些胎盘缺陷的确切性质；将调查原因以及对发育中胚胎的其余部分的后果。最重要的假设是，E2F3在海绵状滋养层细胞和巨型滋养层细胞中的胚外功能对于胚胎发育和胎儿存活是必不可少的。总而言之，这些研究将解决E2F3功能在体内的因果影响。通过这样做，我们希望对E2F3的细胞自主和非自主功能有一个准确的了解，并开发系统来从分子上剖析E2F3作用的分子机制。考虑到癌症在许多方面都可以被认为是一种发育障碍，这些研究的结果将直接影响我们认为E2F3和Rb在肿瘤进展过程中的作用。

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.