Complement Fragment C3a Controls Mutual Cell Attraction during Collective Cell Migration

Abstract

SummaryCollective cell migration is a mode of movement crucial for morphogenesis and cancer metastasis. However, little is known about how migratory cells coordinate collectively. Here we show that mutual cell-cell attraction (named here coattraction) is required to maintain cohesive clusters of migrating mesenchymal cells. Coattraction can counterbalance the natural tendency of cells to disperse via mechanisms such as contact inhibition and epithelial-to-mesenchymal transition. Neural crest cells are coattracted via the complement fragment C3a and its receptor C3aR, revealing an unexpected role of complement proteins in early vertebrate development. Loss of coattraction disrupts collective and coordinated movements of these cells. We propose that coattraction and contact inhibition act in concert to allow cell collectives to self-organize and respond efficiently to external signals, such as chemoattractants and repellents.

Collective mesendoderm migration relies on an intrinsic directionality signal transmitted through cell contacts

“…It is noteworthy that half of the isolated cells actually migrated backward toward the endogenous plate ( Fig. 2 E and F), suggesting that they might be attracted by the group, as recently described in neural crest cells (24). Unfortunately, analysis of cells transplanted laterally or posteriorly to the plate could not confirm this point, as these cells stayed immobile, probably lacking a permissive environment for their migration.…”

Collective cell migration in development

“…5 b). C3a signaling promotes cell-cell interactions, thus contributing to cohesion of the neural crest cell collective, and is necessary for efficient chemotaxis toward SDF-1 (Carmona-Fontaine et al, 2011). In summary, a variety of mechanisms cooperate in migration of CNC cells.…”

“…5 b), the placodal cells adjacent to the neural crest (Theveneau et al, 2010. A third mechanism of autocrine chemotaxis, named coattraction, directly opposes CIL-mediated cell scattering: neural crest cells secrete the complement factor C3a and express its receptor C3aR (Carmona-Fontaine et al, 2011). The C3a/C3aR system acts in an autocrine fashion to attract neural crest cells together, thus counterbalancing the dispersion promoted by CIL (Fig.…”

Molecular cloning and expression analysis of Pleurodeles waltl complement component C3 under normal physiological conditions and environmental stresses

“…Indeed, the expression of complement molecules at the gastrula/ early neurula stage and organ-specific expression patterns during organogenesis were observed in Xenopus laevis (McLin et al, 2008). Furthermore, a recent study showed that Xenopus neural crest cells are coattracted via the complement fragment C3a and its receptor C3aR (Carmona-Fontaine et al, 2011).…”