Luxenburg Chen, Heller Evan, Pasolli H Amalia, Chai Sophia, Nikolova Maria, Stokes Nicole, Fuchs Elaine
The Rockefeller University, Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, New York, New York 10065, USA.
Nat Cell Biol. 2015 May;17(5):592-604. doi: 10.1038/ncb3146. Epub 2015 Apr 27.
During mouse development, core planar cell polarity (PCP) proteins become polarized in the epidermal plane to guide angling/morphogenesis of hair follicles. How PCP is established is poorly understood. Here, we identify a key role for Wdr1 (also known as Aip1), an F-actin-binding protein that enhances cofilin/destrin-mediated F-actin disassembly. We show that cofilin and destrin function redundantly in developing epidermis, but their combined depletion perturbs cell adhesion, cytokinesis, apicobasal polarity and PCP. Although Wdr1 depletion accentuates single-loss-of-cofilin/destrin phenotypes, alone it resembles core PCP mutations. Seeking a mechanism, we find that Wdr1 and cofilin/destrin-mediated actomyosin remodelling are essential for generating or maintaining cortical tension within the developing epidermal sheet and driving the cell shape and planar orientation changes that accompany establishment of PCP in mammalian epidermis. Our findings suggest intriguing evolutionary parallels but mechanistic modifications to the distal wing hinge-mediated mechanical forces that drive cell shape change and orient PCP in the Drosophila wing disc.
在小鼠发育过程中，核心平面细胞极性（PCP）蛋白在表皮平面极化，以引导毛囊的倾斜/形态发生。PCP如何建立尚不清楚。在此，我们确定了Wdr1（也称为Aip1）的关键作用，Wdr1是一种F-肌动蛋白结合蛋白，可增强丝切蛋白/肌动蛋白解聚因子介导的F-肌动蛋白解聚。我们表明，丝切蛋白和肌动蛋白解聚因子在发育中的表皮中功能冗余，但它们的共同缺失会扰乱细胞黏附、胞质分裂、顶基极性和PCP。虽然Wdr1的缺失会加剧丝切蛋白/肌动蛋白解聚因子单基因缺失的表型，但单独缺失Wdr1类似于核心PCP突变。为了寻找一种机制，我们发现Wdr1和丝切蛋白/肌动蛋白解聚因子介导的肌动球蛋白重塑对于在发育中的表皮片中产生或维持皮质张力以及驱动细胞形状和平面方向变化至关重要，这些变化伴随着哺乳动物表皮中PCP的建立。我们的研究结果表明了有趣的进化相似性，但对果蝇翅盘中驱动细胞形状变化和定向PCP的远端翅铰链介导的机械力进行了机制上的修改。
