Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
PLoS Genet. 2019 Jan 30;15(1):e1007955. doi: 10.1371/journal.pgen.1007955. eCollection 2019 Jan.
The Drosophila protocadherins Dachsous and Fat regulate growth and tissue polarity by modulating the levels, membrane localization and polarity of the atypical myosin Dachs. Localization to the apical junctional membrane is critical for Dachs function, and the adapter protein Vamana/Dlish and palmitoyl transferase Approximated are required for Dachs membrane localization. However, how Dachs levels are regulated is poorly understood. Here we identify the early girl gene as playing an essential role in Fat signaling by limiting the levels of Dachs protein. early girl mutants display overgrowth of the wings and reduced cross vein spacing, hallmark features of mutations affecting Fat signaling. Genetic experiments reveal that it functions in parallel with Fat to regulate Dachs. early girl encodes an E3 ubiquitin ligase, physically interacts with Dachs, and regulates its protein stability. Concomitant loss of early girl and approximated results in accumulation of Dachs and Vamana in cytoplasmic punctae, suggesting that it also regulates their trafficking to the apical membrane. Our findings establish a crucial role for early girl in Fat signaling, involving regulation of Dachs and Vamana, two key downstream effectors of this pathway.
果蝇原钙黏蛋白 Dachsous 和 Fat 通过调节非典型肌球蛋白 Dachs 的水平、膜定位和极性来调节生长和组织极性。定位到顶端连接膜对于 Dachs 的功能至关重要，并且适配器蛋白 Vamana/Dlish 和棕榈酰转移酶 Approximated 对于 Dachs 的膜定位是必需的。然而，Dachs 的水平是如何调节的还知之甚少。在这里，我们确定早期女孩基因通过限制 Dachs 蛋白的水平在 Fat 信号转导中发挥重要作用。早期女孩突变体表现出翅膀过度生长和横脉间距减小，这是影响 Fat 信号转导的突变的显著特征。遗传实验表明，它与 Fat 平行作用于 Dachs 的调节。早期女孩基因编码一个 E3 泛素连接酶，与 Dachs 物理相互作用，并调节其蛋白质稳定性。早期女孩和 approximated 的同时缺失导致 Dachs 和 Vamana 在细胞质点状结构中的积累，表明它也调节它们向顶端膜的运输。我们的研究结果确立了早期女孩在 Fat 信号转导中的关键作用，涉及 Dachs 和 Vamana 的调节，这是该途径的两个关键下游效应物。
