MRC National Institute for Medical Research, London
Science for Health
Opposing guidance cues on positioning cell clusters
24 May 2012
Scientists at NIMR have shown that two different signals act as opposing guidance cues in collective cell migration. This work is published in Development.
Collective cell migration, in which cells retain contacts with each other and move as a coherent assembly, is a crucial aspect of embryo development, tissue repair and cancer metastasis. The direction of migration is controlled by the coordinated effects of multiple attractive and repulsive cues. Among many guidance signals, the best known are chemokines, such as stromal cell derived factor-1 (Sdf1), which is a chemoattractant for many cell types through activation of its receptors Cxcr4b and Cxcr7b.
An amenable model to study collective cell migration is provided by the posterior lateral line in zebrafish, which is formed by a cohesive primordium that migrates from head to tail and deposits clusters of cells at intervals. Marie Breau, Duncan Wilson, David Wilkinson and Qiling Xu (pictured) from NIMR’s Division of Developmental Neurobiology, found that prior to the onset of migration the compact state of the primordium is not fully established, as isolated cells with lateral line identity are present posterior to the main primordium. These isolated lateral line cells stay in position such that they fuse with the migrating primordium as it advances. They found that the isolated cells are positioned by antagonistic cues: Sdf1 signaling that attracts lateral line cells towards the posterior is counteracted by fibroblast growth factor (Fgf) signalling that attracts them towards the primordium. These findings reveal a novel chemotactic role for Fgf signalling in which it enables the coalescence of the primordium from an initial fuzzy pattern into a compact group of migrating cells. Since in many tissues, Sdf1 and Fgf signaling play crucial roles in stem cell motility, these findings may also have wider implications for the interplay between these chemoattraction mechanisms in regulating cell organization and cancer progression.
Previous work has revealed indirect roles of Fgf signaling in coordinated migration, in which it regulates epithelial morphogenesis and the expression of chemokine receptors. However, the early steps in which migration is initiated are not known. We made the unexpected finding that rather than the primordium arising as a single group of cells, there are usually some isolated clusters of lateral line cells. We went on to show that the fusion of these cells with the main primordium is enabled by Fgf-mediated chemoattraction towards the primordium, which counteracts Sdf1-mediated posterior migration. The cohesive group of migrating cells is thus formed by a tug of war between opposing cues.
Qiling Xu
Model of opposing effects of Sdf1α/Cxcr4b and Fgf signalling on SPCs.
Click image to view at full-size
(A) In the normal situation, a balance between Sdf1α/Cxcr4b and Fgf/Fgfr1 signalling leads to no net forward or backward movement of SPCs. (B) Cxcr4b-deficient SPCs are unable to sense the Sdf1α chemokine and therefore migrate towards the Fgf-secreting main primordium. (C) Inhibition of Fgf signalling releases the chemoattraction of SPCs, resulting in their Cxcr4b-dependent short distance forward migration on the Sdf1α path.
Original article
Marie A. Breau, Duncan Wilson, David G. Wilkinson and Qiling Xu (2012)
Chemokine and Fgf signalling act as opposing guidance cues in formation of the lateral line primordium
Development 139:2246-2253. Publisher abstract
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