Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Baldiri Reixac, Barcelona, Spain.
PLoS Genet. 2018 Nov 26;14(11):e1007824. doi: 10.1371/journal.pgen.1007824. eCollection 2018 Nov.
The control of the size of internal tubular organs, such as the lungs or vascular system, is critical for proper physiological activity and to prevent disease or malformations. This control incorporates the intrinsic physical anisotropy of tubes to generate proportionate organs that match their function. The exact mechanisms underlying tube size control and how tubular anisotropy is translated at the cellular level are still not fully understood. Here we investigate these mechanisms using the Drosophila tracheal system. We show that the apical polarity protein Crumbs transiently accumulates anisotropically at longitudinal cell junctions during tube elongation. We provide evidence indicating that the accumulation of Crumbs in specific apical domains correlates with apical surface expansion, suggesting a link between the anisotropic accumulation of Crumbs at the cellular level and membrane expansion. We find that Src42A is required for the anisotropic accumulation of Crumbs, thereby identifying the first polarised cell behaviour downstream of Src42A. Our results indicate that Src42A regulates a mechanism that increases the fraction of Crb protein at longitudinal junctions, and genetic interaction experiments are consistent with Crb acting downstream of Src42A in controlling tube size. Collectively, our results suggest a model in which Src42A would sense the inherent anisotropic mechanical tension of the tube and translate it into a polarised Crumbs accumulation, which may promote a bias towards longitudinal membrane expansion, orienting cell elongation and, as a consequence, longitudinal growth at the tissue level. This work provides new insights into the key question of how organ growth is controlled and polarised and unveils the function of two conserved proteins, Crumbs and Src42A, with important roles in development and homeostasis as well as in disease, in this biological process.
管状器官内部大小的控制，如肺部或血管系统，对正常的生理活动和防止疾病或畸形至关重要。这种控制包括了管状结构的固有物理各向异性，以生成与功能相匹配的比例器官。然而，管状大小控制的确切机制以及管状各向异性如何在细胞水平上转化，仍不完全清楚。在这里，我们使用果蝇气管系统来研究这些机制。我们表明，顶端极性蛋白 Crumbs 在管状伸长过程中，在纵向细胞连接处短暂地各向异性积累。我们提供的证据表明，Crumbs 在特定顶端区域的积累与顶端表面的扩展相关，这表明细胞水平上 Crumbs 的各向异性积累与膜扩展之间存在联系。我们发现 Src42A 是 Crumbs 各向异性积累所必需的，从而鉴定了 Src42A 下游的第一个极化细胞行为。我们的结果表明，Src42A 调节了一种机制，该机制增加了 Crb 蛋白在纵向连接处的分数，遗传相互作用实验表明 Crb 作用于 Src42A 下游，控制管状大小。总的来说，我们的结果表明，Src42A 会感知管状结构固有的各向异性机械张力，并将其转化为极化的 Crumbs 积累，这可能促进纵向膜扩展的偏向性，从而定向细胞伸长，并因此在组织水平上促进纵向生长。这项工作为器官生长如何被控制和极化的关键问题提供了新的见解，并揭示了两个保守蛋白 Crumbs 和 Src42A 的功能，它们在发育和稳态以及疾病中具有重要作用，在这个生物学过程中。
