Department of Genetics and Development, Columbia University Medical Center, New York, New York, United States of America.
PLoS Genet. 2010 Oct 28;6(10):e1001176. doi: 10.1371/journal.pgen.1001176.
The actin depolymerizing factors (ADFs) play important roles in several cellular processes that require cytoskeletal rearrangements, such as cell migration, but little is known about the in vivo functions of ADFs in developmental events like branching morphogenesis. While the molecular control of ureteric bud (UB) branching during kidney development has been extensively studied, the detailed cellular events underlying this process remain poorly understood. To gain insight into the role of actin cytoskeletal dynamics during renal branching morphogenesis, we studied the functional requirements for the closely related ADFs cofilin1 (Cfl1) and destrin (Dstn) during mouse development. Either deletion of Cfl1 in UB epithelium or an inactivating mutation in Dstn has no effect on renal morphogenesis, but simultaneous lack of both genes arrests branching morphogenesis at an early stage, revealing considerable functional overlap between cofilin1 and destrin. Lack of Cfl1 and Dstn in the UB causes accumulation of filamentous actin, disruption of normal epithelial organization, and defects in cell migration. Animals with less severe combinations of mutant Cfl1 and Dstn alleles, which retain one wild-type Cfl1 or Dstn allele, display abnormalities including ureter duplication, renal hypoplasia, and abnormal kidney shape. The results indicate that ADF activity, provided by either cofilin1 or destrin, is essential in UB epithelial cells for normal growth and branching.
肌动蛋白解聚因子（ADFs）在需要细胞骨架重排的几种细胞过程中发挥重要作用，例如细胞迁移，但对于 ADF 在分支形态发生等发育事件中的体内功能知之甚少。虽然输尿管芽（UB）分支在肾脏发育过程中的分子控制已经得到广泛研究，但这一过程背后的详细细胞事件仍知之甚少。为了深入了解肌动蛋白细胞骨架动力学在肾脏分支形态发生中的作用，我们研究了密切相关的 ADFs 细丝蛋白 1（Cfl1）和 destrin（Dstn）在小鼠发育过程中的功能要求。UB 上皮细胞中 Cfl1 的缺失或 Dstn 的失活突变对肾脏形态发生均无影响，但这两种基因的同时缺失会使分支形态发生在早期阶段停止，表明 Cfl1 和 Dstn 之间存在相当大的功能重叠。UB 中缺乏 Cfl1 和 Dstn 会导致丝状肌动蛋白的积累、正常上皮组织的破坏以及细胞迁移缺陷。具有更严重的 Cfl1 和 Dstn 突变等位基因组合的动物，保留一个野生型 Cfl1 或 Dstn 等位基因，会显示出异常，包括输尿管重复、肾脏发育不全和肾脏形状异常。结果表明，ADF 活性由 Cfl1 或 Dstn 提供，对于 UB 上皮细胞的正常生长和分支是必不可少的。
