Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA; Department of Computational Mathematics, Science, and Engineering, Michigan State University, East Lansing, MI, USA.
Cells Dev. 2022 Mar;169:203747. doi: 10.1016/j.cdev.2021.203747. Epub 2021 Sep 25.
Specification of cellular polarity is vital to normal tissue development and function. Pioneering studies in Drosophila and C. elegans have elucidated the composition and dynamics of protein complexes critical for establishment of cell polarity, which is manifest in processes such as cell migration and asymmetric cell division. Conserved throughout metazoans, planar cell polarity (PCP) genes are implicated in disease, including neural tube closure defects associated with mutations in VANGL1/2. PCP protein regulation is well studied; however, relatively little is known about transcriptional regulation of these genes. Our earlier study revealed an unexpected role for the fly Rbf1 retinoblastoma corepressor protein, a regulator of cell cycle genes, in transcriptional regulation of polarity genes. Here we analyze the physiological relevance of the role of E2F/Rbf proteins in the transcription of the key core polarity gene Vang. Targeted mutations to the E2F site within the Vang promoter disrupts binding of E2F/Rbf proteins in vivo, leading to polarity defects in wing hairs. E2F regulation of Vang is supported by the requirement for this motif in a reporter gene. Interestingly, the promoter is repressed by overexpression of E2F1, a transcription factor generally identified as an activator. Consistent with the regulation of this polarity gene by E2F and Rbf factors, expression of Vang and other polarity genes is found to peak in G2/M phase in cells of the embryo and wing imaginal disc, suggesting that cell cycle signals may play a role in regulation of these genes. These findings suggest that the E2F/Rbf complex mechanistically links cell proliferation and polarity.
细胞极性的特化对于正常组织的发育和功能至关重要。果蝇和秀丽隐杆线虫的开创性研究阐明了建立细胞极性的关键蛋白复合物的组成和动态，这些过程表现在细胞迁移和不对称细胞分裂等过程中。在后生动物中保守的平面细胞极性（PCP）基因与疾病有关，包括与 VANGL1/2 突变相关的神经管闭合缺陷。PCP 蛋白的调节已经得到了很好的研究；然而，关于这些基因的转录调节相对知之甚少。我们之前的研究揭示了果蝇 Rbf1 视网膜母细胞瘤核心抑制蛋白作为细胞周期基因调节剂的一个意想不到的作用，在极性基因的转录调节中发挥作用。在这里，我们分析了 E2F/Rbf 蛋白在关键核心极性基因 Vang 转录中的作用的生理相关性。在 Vang 启动子内的 E2F 位点上的靶向突变破坏了体内 E2F/Rbf 蛋白的结合，导致翅膀毛发的极性缺陷。E2F 对 Vang 的调节得到了该基序在报告基因中的作用的支持。有趣的是，E2F1 的过表达抑制了启动子，E2F1 是一种通常被认为是激活剂的转录因子。与 E2F 和 Rbf 因子对这个极性基因的调节一致，在胚胎和翅膀 imaginal disc 的细胞中发现 Vang 和其他极性基因的表达在 G2/M 期达到峰值，这表明细胞周期信号可能在这些基因的调节中发挥作用。这些发现表明，E2F/Rbf 复合物在机制上连接了细胞增殖和极性。
