Sticking to a plan: adhesion and signaling control spatial organization of cells within migrating collectives

Abstract

Collective cell migration is required in a vast array of biological phenomena, including organogenesis and embryonic development. The mechanisms that underlie collective cell migration not only involve the morphogenetic changes associated with single cell migration, but also require the maintenance of cell-cell junctions during movement. Additionally, cell shape changes and polarity must be coordinated in a multicellular manner in order to preserve directional movement in the migrating cohort, and often relates to multiple functions of common signaling pathways. In this review, we summarize the current understanding of the mechanisms underlying higher order tissue organization during migration, with particular focus on the interplay between cell adhesion and signaling that we propose can be tuned to support different types of collective movements.

Figure 1.. General model for collective cell migration and examples.

A) Directional movement of a cell collective requires both intercellular adhesions (via adherens junctions) and interactions with the substrate/environment (via focal adhesions). When exposed to a guidance cue, leader cells at the front typically lose epithelial character and become more protrusive, which is accompanied by a loss of intercellular adhesive contact and an increase in polarized F-actin to form protrusions. B) The epithelial to mesenchymal transition is marked by dynamic adjustments to adhesive states and changes to overall spatial arrangement. Shown are some examples of tissues that run the gamut of epithelial to mesenchymal characteristics, including epithelial sheets, Drosophila border cells, neural crest cells, and single cells (such as primordial germ cells).

Figure 2.. Different modes of collective migration mediated by different aspects of intracellular signaling.

A) Drosophila Follicle cell migration is mediated by planar polarized Fat2 and Lar. Fat2 expression in the trailing edge of cells ahead induce protrusive activity in the leading edge of cells behind, while Lar activity in the leading edge of the cells behind mediate trailing edge retraction in the preceding cell. B) High Rap1 activity suppresses Hpo activity in Drosophila border cells, which allows for Ena-mediated F-actin polymerization to form directional protrusions. In cells with low Rap1 activity, Hpo signaling suppresses Ena. C) Mesoderm spreading in gastrulating Drosophila embryos involves a MET that culminates in a single layer of cells. This process is supported by basal expression of the β-integrin subunit Mys. D) In neural crest cells, contraction of an actomyosin cable at the rear of the cell cohort drives intercalation, thus supporting directed movement. This contractility is inhibited in the front by exposure to SDF1 cue, ensuring that contractility is polarized to the rear of the group of cells.