A Rho-GTPase based model explains spontaneous collective migration of neural crest cell clusters

Abstract

We propose a model to explain the spontaneous collective migration of neural crest cells in the absence of an external gradient of chemoattractants. The model is based on the dynamical interaction between Rac1 and RhoA that is known to regulate the polarization, contact inhibition and co-attraction of neural crest cells. Coupling the reaction-diffusion equations for active and inactive Rac1 and RhoA on the cell membrane with a mechanical model for the overdamped motion of membrane vertices, we show that co-attraction and contact inhibition cooperate to produce persistence of polarity in a cluster of neural crest cells by suppressing the random onset of Rac1 hotspots that may mature into new protrusion fronts. This produces persistent directional migration of cell clusters in corridors. Our model confirms a prior hypothesis that co-attraction and contact inhibition are key to spontaneous collective migration, and provides an explanation of their cooperative working mechanism in terms of Rho GTPase signaling. The model shows that the spontaneous migration is more robust for larger clusters, and is most efficient in a corridor of optimal confinement.

Neural crest migration with continuous cell states

“…Understanding their migration is important to identify the causes for birth defects, and they also provide a model system to study the invasive migration of cancer cells, especially the neural crest derived melanoma 5 [1,2,3]. Mechanisms of neural crest cell migration have been studied in a variety of model organisms, and multiple groups have approached the problem with mathematical modelling [4,5,6,7,8,9,10,11,12,13].…”

Cell–substrate mechanics guide collective cell migration through intercellular adhesion: a dynamic finite element cellular model

“…Recently, computational models have become increasingly useful to complement experimental observations towards understanding the mechanisms of collective cell migration. A number of computational cell models have been developed to study the mechanical interactions between cells or between cell and ECM (Albert and Schwarz, 2016;Basan et al, 2013;Checa et al, 2015;Drasdo and Hoehme, 2012;Hoehme and Drasdo, 2010;Hutson et al, 2009;Kabla, 2012;Kachalo et al, 2015;Kim et al, 2018Kim et al, , 2015Lee and Wolgemuth, 2011;Lee et al, 2017;Marée et al, 2007;Merchant et al, 2018;Nagai and Honda, 2009;Nematbakhsh et al, 2017;Sandersius et al, 2011;Van Liedekerke et al, 2019;Vermolen and Gefen, 2015;Vitorino et al, 2011;Zhao et al, 2013). However, these models have limitations.…”

“…Other models mimic the cellular mechanics using arbitrarily imposed Morse potential which is unrealistic at cellular level (Nematbakhsh et al, 2017;Sandersius et al, 2011). In many cases, details of the intercellular adhesions are not considered (Basan et al, 2013;Checa et al, 2015;Drasdo and Hoehme, 2012;Hoehme and Drasdo, 2010;Hutson et al, 2009;Kabla, 2012;Kim et al, 2018Kim et al, , 2015Lee and Wolgemuth, 2011;Lee et al, 2017;Merchant et al, 2018;Nagai and Honda, 2009;Van Liedekerke et al, 2019;Vermolen and Gefen, 2015;Vitorino et al, 2011).…”

Force-induced repolarization of an active crawler

“…Building reliable links between repolarization mechanisms and measurable biophysical parameters is fundamental for the control of development, integrity and regeneration of living organisms [4][5][6][7][8][9][10][11][12][13]. A broadly accepted mechanism of force-induced repolarization relies on a reaction-diffusion instability involving several biochemical agents, in particular, Rho-GTPases, which control the motor activity in the cytoskeleton [14][15][16]. In this paper we propose an alternative mechanism by showing that the application of an external force can lead to mechanical repolarization involving relocation of molecular motors, without invoking any biochemical signal transduction.…”