In vivo confinement promotes collective migration of neural crest cells

Abstract

Collective cell migration is fundamental throughout development and in many diseases. Spatial confinement using micropatterns has been shown to promote collective cell migration in vitro, but its effect in vivo remains unclear. Combining computational and experimental approaches, we show that the in vivo collective migration of neural crest cells (NCCs) depends on such confinement. We demonstrate that confinement may be imposed by the spatiotemporal distribution of a nonpermissive substrate provided by versican, an extracellular matrix molecule previously proposed to have contrasting roles: barrier or promoter of NCC migration. We resolve the controversy by demonstrating that versican works as an inhibitor of NCC migration and also acts as a guiding cue by forming exclusionary boundaries. Our model predicts an optimal number of cells in a given confinement width to allow for directional migration. This optimum coincides with the width of neural crest migratory streams analyzed across different species, proposing an explanation for the highly conserved nature of NCC streams during development.

Collective gradient sensing and chemotaxis: modeling and recent developments

“…Many aspects of collective gradient sensing in neural crest have been confirmed to function similarly within Xenopus and the in vitro experiments discussed above [47, 49, 50]. However, measurements of chick cranial neural crest in vivo by McLennan et al also show that cells at the front of the invading neural crest express different genes than trailing cells [51].…”

“…(Though I note nematic alignment is also a possibility [68, 69]. ) If cells within a cluster become aligned and travel in a consistent direction even in the absence of a signal, as appears to be the case for neural crest clusters [2, 50], then individual cells that measure the gradient can lead to the entire cluster following the gradient.…”

Neural crest and cancer: Divergent travelers on similar paths

“…More recently, the ECM protein versican was shown to act as a guiding factor in NC migration (Szabó et al, 2016). Versican is inhibitory to NCC migration in vitro , whereas loss of versican in Xenopus embryos results in NCCs being unable to migrate dorsolaterally along the embryo (Szabó et al, 2016).…”

“…Versican is inhibitory to NCC migration in vitro , whereas loss of versican in Xenopus embryos results in NCCs being unable to migrate dorsolaterally along the embryo (Szabó et al, 2016). These results suggest the possibility that versican’s inhibitory effect could be required for funneling NCCs into migratory streams.…”

<b><i>Xenopus</i></b>: An Undervalued Model Organism to Study and Model Human Genetic Disease

“…The possibility to directly observe embryonic development and even perform live cell imaging has been extensively used with great success in zebrafish. However, this is not a unique feature of zebrafish; kidney development and neural crest cell migration, for example, have been directly imaged in live frog em- bryos at great temporal and spatial resolution [Lienkamp et al, 2010[Lienkamp et al, , 2012Szabó et al, 2016;Getwan and Lienkamp, 2017]. Zebrafish also have certain organ-specific limitations.…”