Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Baldiri Reixac, 4-8, 08028 Barcelona, Spain.
Development. 2014 Feb;141(4):929-39. doi: 10.1242/dev.103218.
A key challenge in normal development and in disease is to elucidate the mechanisms of cell migration. Here we approach this question using the tracheal system of Drosophila as a model. Tracheal cell migration requires the Breathless/FGFR pathway; however, how the pathway induces migration remains poorly understood. We find that the Breathless pathway upregulates singed at the tip of tracheal branches, and that this regulation is functionally relevant. singed encodes Drosophila Fascin, which belongs to a conserved family of actin-bundling proteins involved in cancer progression and metastasis upon misregulation. We show that singed is required for filopodia stiffness and proper morphology of tracheal tip cells, defects that correlate with an abnormal actin organisation. We propose that singed-regulated filopodia and cell fronts are required for timely and guided branch migration and for terminal branching and branch fusion. We find that singed requirements rely on its actin-bundling activity controlled by phosphorylation, and that active Singed can promote tip cell features. Furthermore, we find that singed acts in concert with forked, another actin cross-linker. The absence of both cross-linkers further stresses the relevance of tip cell morphology and filopodia for tracheal development. In summary, our results on the one hand reveal a previously undescribed role for forked in the organisation of transient actin structures such as filopodia, and on the other hand identify singed as a new target of Breathless signal, establishing a link between guidance cues, the actin cytoskeleton and tracheal morphogenesis.
在正常发育和疾病中，一个关键的挑战是阐明细胞迁移的机制。在这里，我们使用果蝇的气管系统作为模型来解决这个问题。气管细胞的迁移需要 Breathless/FGFR 途径；然而，该途径如何诱导迁移仍知之甚少。我们发现 Breathless 途径在上调气管分支尖端的 singed，并且这种调节具有功能相关性。singed 编码果蝇 Fascin，它属于一个保守的肌动蛋白束蛋白家族，在失调时参与癌症进展和转移。我们表明 singed 是丝状伪足的刚性和气管尖端细胞的适当形态所必需的，这些缺陷与异常的肌动蛋白组织相关。我们提出，singed 调节的丝状伪足和细胞前缘是分支迁移、末端分支和分支融合的及时和有指导的所需条件。我们发现，singed 的需求依赖于其由磷酸化控制的肌动蛋白束形成活性，并且活性 Singed 可以促进尖端细胞特征。此外，我们发现 singed 与叉头蛋白（另一种肌动蛋白交联蛋白）协同作用。这两种交联蛋白的缺失进一步强调了尖端细胞形态和丝状伪足对于气管发育的重要性。总之，我们的结果一方面揭示了叉头蛋白在丝状伪足等短暂肌动蛋白结构的组织中的一个以前未描述的作用，另一方面鉴定了 singed 作为 Breathless 信号的一个新靶标，在指导线索、肌动蛋白细胞骨架和气管形态发生之间建立了联系。
