Mathematical modelling predicts novel mechanisms of stream confinement from Trail/Colec12/Dan in the collective migration of cranial neural crest cells

Background In vertebrate embryogenesis, cranial neural crest cells (CNCCs) migrate along discrete pathways. Analyses in the chick have identified key molecular candidates for the confinement of CNCC migration to stereo-typical pathways as Colec12, Trail, and Dan. The effects of these factors on CNCCs in vitro are known, but how they confine migration to discrete streams in vivo remains poorly-understood. Here, we propose and test several hypothetical mechanisms by which these factors confine cell streams and maintain coherent migration, simulating an expanded agent-based model for collective CNCC migration. Results Model simulations suggest that Trail enhances adhesion between CNCCs, facilitating movement towards stereotypical migratory pathways, whereas Colec12 confines CNCCs by inducing longer, branched filopodia that facilitate movement down Colec12 gradients and re-connections with streams. Moreover, we find that Trail and Colec12 facilitate the exchange of CNCCs and the formation of CNCC-bridges between adjacent streams that are observed in vivo but poorly-understood mechanistically. Finally, we predict that Dan increases the coherence of streams by modulating the speed of CNCCs at the leading edge of collectives to prevent escape. Conclusions Our work highlights the importance of Trail, Colec12, and Dan in CNCC migration and predicts novel mechanisms for the confinement of CNCCs to stereotypical pathways in vivo .