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Collective cell migration underlies morphogenesis, wound healing and cancer invasion1,2. Most directed migration in vivo has been attributed to chemotaxis, whereby cells follow a chemical gradient3-5. Cells can also follow a stiffness gradient in vitro, a process called durotaxis3,4,6-8, but evidence for durotaxis in vivo is lacking6. Here we show that in Xenopus laevis the neural crest-an embryonic cell populationself-generates a stiffness gradient in the adjacent placodal tissue, and follows this gradient by durotaxis. The gradient moves with the neural crest, which is continually pursuing a retreating region of high substrate stiffness. Mechanistically, the neural crest induces the gradient due to N-cadherin interactions with the placodes and senses the gradient through cell-matrix adhesions, resulting in polarized Rac activity and actomyosin contractility, which coordinates durotaxis. Durotaxis synergizes with chemotaxis, cooperatively polarizing actomyosin machinery ofthe cell group to prompt efficient directional collective cell migration in vivo. These results show that durotaxis and dynamic stiffness gradients exist in vivo, and gradients of chemical and mechanical signals cooperate to achieve efficient directional cell migration.
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Collective cell migration is essential for morphogenesis, tissue remodelling and cancer invasion1,2. Most cell migration in vivo is directional, with cells guided by extracellular signals1,3,4. Chemotaxis, the well-established process by which cells follow gradients of soluble chemical cues, is the main mechanism proposed to direct cell migration in vivo1,3-5. Extracellular mechanics are now also believed to contribute to cell guidance9. Some cell types can individually or collectively follow gradients in the stiffness of their substrate, a process that is known as durotaxis3,4,6-9. However, although stiffness of biological tissues inevitably presents heterogeneities10, difficulties of accessing, measuring and manipulating stiffness in vivo have meant there is still scarce evidence that durotaxis occurs in vivo, despite more than 20 years passing since its discovery in vitro6,7. Moreover, it is unclear how a stiffness gradient can be formed in vivo and how gradients of chemical and mechanical cues might interplay in the complex three-dimensional in vivo environment to coordinate directional cell migration.
A dynamic substrate stiffness gradient
The neural crest is an embryonic stem-cell population that originates in the dorsal aspect of the neural tube and collectively migrates long distances through the embryo. Recent work using X. laevis embryos demonstrating that mechanical stiffening...