Filopodia-based contact stimulated collective migration drives tissue morphogenesis

Abstract

Cells migrate collectively to form tissues and organs during morphogenesis. Contact inhibition of locomotion (CIL) drives collective migration by inhibiting lamellipodial protrusions at cell-cell contacts and promoting polarization at the leading edge. Here, we report on a CIL-related collective cell behavior of myotubes that lack lamellipodial protrusions, but instead use filopodia to move as a cohesive cluster in a formin-dependent manner. Genetic, pharmacological and mechanical perturbation analyses reveal essential roles of Rac2, Cdc42 and Rho1 in myotube migration. They differentially control not only protrusion dynamics but also cell-matrix adhesion formation. Here, active Rho1 GTPase localizes at retracting free edge filopodia. Rok-dependent actomyosin contractility does not mediate a contraction of protrusions at cell-cell contacts but likely plays an important role in the constriction of supracellular actin cables. We propose that contact-dependent asymmetry of cell-matrix adhesion drives directional movement, whereas contractile actin cables contribute to the integrity of the migrating cell cluster.

Collective cell migration driven by filopodia—New insights from the social behavior of myotubes

“…However, close examination of the migrating myotubes employing the newly established 4D imaging methods revealed that all myotubes resembled each other in terms of cell protrusion. [4] Unlike border cell migration, no subset of cells seemed to exclusively react to an outside gradient. Instead, myotubes likely self-regulate their behavior.…”

“…[43][44][45] Recent observations in vitro and in vivo have further challenged our current view of the function of filopodia in migrating cells. [4,46] Adebowale and colleagues found that filopodial protrusions mediate migration of cultured human cancer cells on soft, fast-relaxing substrates suggesting that filopodia-based migration may play a key role in cancer metastasis in physiologically relevant 3D environments [46] (Figure 1A). Recent livecell-imaging experiments further showed that filopodia play not only an important role in cancer progression, but also in collective migration of testis nascent myotubes during Drosophila development (Figure 1D).…”

“…Recently, the testis myotube migration system was introduced. [4] To put it into context, some well-established models will be summarized in this section followed by a description of the myotube system highlighting new concepts of self-regulation in collective cell migration.…”

“…Detailed observation employing live-cell 4D imaging of cultured pupal Drosophila testis revealed that myotubes seem likewise mesenchymal and homogeneous. [4] Before migration starts, until 28-30 h after pupae formation (APF), the anlagen of the testis and the rest of the genital tract lie separately inside the body cavity. The so-called genital imaginal disc contains myoblasts that later build the musculature of the entire system.…”

“…Here, they are quickly disassembled muscular sheet (see also Figure 2C). [4,47] Migrating myotubes completely lack lamellipodial protrusions, but instead use filopodia to move as a cohesive cluster in a formin-dependent manner. Interestingly, pharmacologic and genetic of Arp2/3 complex function revealed that the Arp2/3 complex it is not completely negligible for filopodia-based myotube migration.…”