Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the <em>Drosophila</em> Retina

Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumor suppressor pathway, pRB functions to maintain the terminally differentiated state. We show that mutations in the Hippo signaling pathway, wts or hpo, trigger widespread dedifferentiation of rbf mutant cells in the Drosophila eye. Initially, rbf wts or rbf hpo double mutant cells are morphologically indistinguishable from their wild-type counterparts as they properly differentiate into photoreceptors, form axonal projections, and express late neuronal markers. However, the double mutant cells cannot maintain their neuronal identity, dedifferentiate, and thus become uncommitted eye specific cells. Surprisingly, this dedifferentiation is fully independent of cell cycle exit defects and occurs even when inappropriate proliferation is fully blocked by a de2f1 mutation. Thus, our results reveal the novel involvement of the pRB pathway during the maintenance of a differentiated state and suggest that terminally differentiated Rb mutant cells are intrinsically prone to dedifferentiation, can be converted to progenitor cells, and thus contribute to cancer advancement.视网膜母细胞瘤（Retinoblastoma，pRB）通路的功能性失活是肿瘤发生过程中的早期且必需事件。pRB的重要性通常被归因于其介导细胞周期退出的能力。本研究证实，在不依赖细胞周期退出调控的前提下，pRB可与Hippo肿瘤抑制通路（Hippo tumor suppressor pathway）协同发挥作用，维持细胞的终末分化状态。我们发现，果蝇复眼（Drosophila eye）中Hippo信号通路的突变体wts或hpo，会诱导rbf突变细胞发生广泛的去分化。在初始阶段，rbf wts或rbf hpo双突变体细胞可正常分化为感光细胞（photoreceptors）、形成轴突投射（axonal projections）并表达晚期神经元标记物（neuronal markers），其形态学特征与野生型对照细胞并无显著差异。然而，此类双突变体细胞无法维持其神经元身份，最终发生去分化，转变为未定型的眼特异性细胞。令人意外的是，该去分化过程完全不依赖细胞周期退出缺陷，即便通过de2f1突变完全阻断异常增殖，该过程仍可正常发生。综上，本研究揭示了pRB通路在维持细胞分化状态中的全新功能，并表明终末分化的Rb突变体细胞存在内在的去分化倾向，可转化为祖细胞，进而推动肿瘤进展。