Leader Cells Define Directionality of Trunk but Not Cranial Neural Crest Cell Migration

摘要

class="head no_bottom_margin" id="sec1title">IntroductionCell migration is fundamental for life, from organ formation to tissue repair and regeneration. Cells can migrate individually or collectively. Collective cell migration may endow cancer cells with an increased invasion capacity, which can result in aggressive tumor metastasis (). Cells migrating collectively maintain contact and read guidance cues cooperatively. These groups can adopt a range of spatial arrangements, from small numbers of loosely connected mesenchymal cells, to large masses of tightly associated cells (). Within these arrangements, cells may dynamically change position and rely on cell-cell interaction to determine directionality or be firmly positioned and play specific roles with leading cells directing movement (, ).Neural crest (NC) cells are a highly migratory embryonic population that shares many characteristics of metastatic cells (). Historically, NC cells have been described as cells that migrate individually (), but recent work on chick and Xenopus embryos have demonstrated that cranial NC (CNC) cells migrate collectively. Experiments in Xenopus suggest that a combination of mechanisms imbue the group with polarity, cohesion, and overall directionality (contact inhibition of locomotion, co-attraction, collective chemotaxis, and interaction with surrounding tissues), leading to the proposition that all CNC cells are equally capable of taking the leader position, but it is the interaction between cells that endows the group with polarity and persistent migration (). By contrast, mathematical modeling and gene expression analyses of chick CNC cells have given rise to an alternative proposition, whereby cells adopt different identities depending on their position within the group. Leader cells, at the front of the group, are the only cells capable of directing migration, while trailers are guided by direct contact to a leader or to a trailer cell that has made contact with a leader (, ).While CNC cells have been the subject of intense research, trunk NC (TNC) cells have attracted less attention. TNC cells migrate in two waves. First, they invade the space between the somites and the neural tubeotochord, named the medial pathway. Subsequently, TNC cells move between the ectoderm and the somites into the lateral pathway (). Live imaging in chick has revealed that TNC cells migrating into the medial pathway do so in streams with close cell-cell interaction (, ). Moreover, video-microscopy analysis of zebrafish TNC cells has shown that NC-NC cell contact leads to collapse of membrane protrusions (), similar to the mechanism of contact inhibition during CNC cell migration (). While these studies suggest that cell-cell interaction may also play a role during TNC cell migration, the topology, dynamics, and cellular regulation of migration remain largely unknown.To better understand TNC cell migration and distinguish between the different models proposed to control CNC cell migration, we have conducted in vivo imaging and quantitative analysis in chick and zebrafish embryos. We found that all CNC cells present similar migratory behaviors and that leader cells are not a permanent population at the front of the group: instead, cells readily intermingle as they migrate, integrating into the leading edge only transiently. Moreover, laser ablation experiments in zebrafish embryos show that leader cells are not required for CNC cell directional migration. TNC cells, on the other hand, present a remarkably different migratory behavior. They move as single cell chains with division of labor: leader cells are permanently positioned at the front, instructing directionality to the entire group, while follower cells form the body of the chain and require cell-cell contact for migration. Leader and follower identities are defined before the initiation of migration and remain fixed thereafter. Our data show that TNC cells are a heterogeneous population at the outset of migration, consistent with a mechanism of fate restriction defining their migratory paths and behaviors ().