Raza Qanber, Jacobs J Roger
Department of Biology, McMaster University, 1280 Main St W, Hamilton, ON, Canada L8S 4L8.
Department of Biology, McMaster University, 1280 Main St W, Hamilton, ON, Canada L8S 4L8.
Dev Biol. 2016 Nov 15;419(2):285-297. doi: 10.1016/j.ydbio.2016.09.005. Epub 2016 Sep 9.
Collective cell migration is the coordinated movement of cells, which organize tissues during morphogenesis, repair and some cancers. The motile cell membrane of the advancing front in collective cell migration is termed the Leading Edge. The embryonic development of the vertebrate and Drosophila hearts are both characterized by the coordinated medial migration of a bilateral cluster of mesodermal cells. In Drosophila, the cardioblasts form cohesive bilateral rows that migrate collectively as a unit towards the dorsal midline to form the dorsal vessel. We have characterized the collective cell migration of cardioblasts as an in vivo quantitative model to study the behaviour of the Leading Edge. We investigated whether guidance signalling through Slit and Netrin pathways plays a role in cell migration during heart development. Through time-lapse imaging and quantitative assessment of migratory behaviour of the cardioblasts in loss-of-function mutants, we demonstrate that both Slit and Netrin mediated signals are autonomously and concomitantly required to maximize migration velocity, filopodial and lamellipodial activities. Additionally, we show that another Slit and Netrin receptor, Dscam1, the role of which during heart development was previously unknown, is required for both normal migration of cardioblasts and luminal expansion. Leading edge behaviour analysis revealed a dosage dependent genetic interaction between Slit and Netrin receptors suggesting that downstream signalling through these receptors converge on a common output that increases leading edge activity of the cardioblasts. Finally, we found that guidance signalling maintains the balance between epithelial and mesenchymal characteristics of the migrating cardioblasts.
集体细胞迁移是细胞的协同运动，在形态发生、组织修复以及某些癌症过程中对组织进行组织化。在集体细胞迁移中，前进前沿的运动细胞膜被称为前缘。脊椎动物和果蝇心脏的胚胎发育都以中胚层细胞双侧簇的协同向内侧迁移为特征。在果蝇中，成 cardioblasts 细胞形成紧密的双侧行，作为一个整体集体迁移至背中线以形成背血管。我们已将成 cardioblasts 细胞的集体细胞迁移表征为一种体内定量模型，以研究前缘的行为。我们研究了通过 Slit 和 Netrin 途径的导向信号在心脏发育过程中的细胞迁移中是否发挥作用。通过对功能缺失突变体中成 cardioblasts 细胞迁移行为的延时成像和定量评估，我们证明 Slit 和 Netrin 介导的信号对于最大化迁移速度、丝状伪足和片状伪足活动都是自主且同时必需的。此外，我们表明另一种 Slit 和 Netrin 受体 Dscam1（其在心脏发育过程中的作用此前未知）对于成 cardioblasts 细胞的正常迁移和管腔扩张都是必需的。前缘行为分析揭示了 Slit 和 Netrin 受体之间的剂量依赖性遗传相互作用，表明通过这些受体的下游信号汇聚于一个共同输出，该输出增加了成 cardioblasts 细胞的前缘活性。最后，我们发现导向信号维持了迁移的成 cardioblasts 细胞上皮和间充质特征之间的平衡。
