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In vivo topology converts competition for cell-matrix adhesion into directional migration

Fernanda Bajanca, Nadege Gouignard, Charlotte Colle, Maddy Parsons, Roberto Mayor, Eric Theveneau

Preprint posted on February 21, 2018 https://www.biorxiv.org/content/early/2018/01/31/256255

Gradients not required? A recent preprint describes how Xenopus neural crest cells migrate during development: patterning of ECM composition provides directional information, while the 'attractant' Sdf1 is important for migration.

Selected by Helen Zenner

Background 

The control of directed cell migration has been an intensively studied subject in developmental biology for many years.  Different mechanisms of control, such as long-range morphogen gradients and extracellular matrix (ECM)-mediated contact guidance, have been proposed from both in vitro and in vivo work. Whilst some of these mechanisms can individually explain directed migration in relatively simple structures, it is increasingly clear that an integration of will be required to organise migration in more complex structures. This preprint aims to address this issue, using two well-studied regulators of directed cell migration, stromal-cell derived factor 1 (Sdf1) and Semaphorins, which act as positive and negative regulators respectively.

Key Findings

In this study, the authors demonstrate that in Xenopus cephalic neural crest cells (NCCs), an antagonism exists between Semaphorins and stromal-cell derived factor 1 (Sdf1).  This antagonism works via the Rho GTPase, Rac1, which is activated by Sdf1, whilst Sema3A reduces its activity.  At a single cell level, treatment with Sema3A reduces cell-matrix adhesion compared with control cells, explaining why cells fail to migrate in Sema-positive regions.  This effect is reversed by addition of Sdf1, or by activating Rac1 via stimulation of integrins.

However, the Sem3a-Sdf1 antagonism is context-dependent since it only exists on fibronectin:  Sdf1 is unable to rescue the effects of Sema3a treatment on a collagen-laminin mix.  Most interestingly, they find that fibronectin distribution in Xenopus correlates with the migration path of NCCs, suggesting the specific distribution of ECM may be important for directing migration.  Indeed, using grafting experiments, the authors found that cells unable to sense Sdf1 were still able to follow the correct migratory pathway, provided that integrin signalling had been activated to initiate migration. This indicates that the non-homogenous nature of the ECM provides key directional information, while Semaphorins confine the path of migrating cells and Sdf1 primarily primarily plays a role in initiating migration.

Importance

One of the strengths of this paper is the combination of in vitro and in vivo work, which allows them to dissect the context-dependent effects of Sdf1 and Semaphorins.  Since Sdf1, Sema3A, and Sema3F are linked with many different cancers, they are considered to be putative therapeutic targets.  The paper highlights the importance of considering the context and integration of signals, since interventions could have differential effects dependent on location.  Furthermore, this work indicates that it may be necessary to re-evaluate the assumption that these molecules act in long-range gradients.

Open Questions

  1. Is this phenomenon restricted to Xenopus NCCs? In other complex tissues, do biased distributions of matrix play important role in directing migration, dispensing with the need to maintain gradients of attractants as the tissue is changing shape?
  2. What is the relationship between Semaphorins, Sdf1 and the ECM in other species?

 

Tags: cell migration, ecm, frog, signalling

Posted on: 21st February 2018 , updated on: 23rd February 2018

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