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Directed cell migration is essential all along an individual's life, from embryogenesis to tissue repair and cancer metastasis. Thus, due to its biomedical relevance, directed cell migration is currently under intense research. Directed cell migration has been shown to be driven by an assortment of external biasing cues, ranging from gradients of soluble (chemotaxis) to bound (haptotaxis) molecules. In addition to molecular gradients, gradients of mechanical properties (duro/mechanotaxis), electric fields (electro/galvanotaxis) as well as iterative biases in the environment topology (ratchetaxis) have been shown to be able to direct cell migration. Since cells migrating in vivo are exposed to a challenging environment composed of a convolution of biochemical, biophysical, and topological cues, it is highly unlikely that cell migration would be guided by an individual type of "taxis." This is especially true since numerous molecular players involved in the cellular response to these biasing cues are often recycled, serving as sensor or transducer of both biochemical and biophysical signals. In this review, we confront literature on Xenopus cephalic neural crest cells with that of other cell types to discuss the relevance of the current categorization of cell guidance strategies. Furthermore, we emphasize that while studying individual biasing signals is informative, the hard truth is that cells migrate by performing a sort of "mixotaxis," where they integrate and coordinate multiple inputs through shared molecular effectors to ensure robustness of directed cell motion.
FIGURE 1. Overview of neural crest migration. (A–C) Diagrams depicting the position of NC cells (shades of brown to magenta) with respect to the placodal region (light blue) at pre-migration (stage 18), early migration (stage 21), and late migration (stage 25). EMT is progressively implemented as NC migration proceeds. Brown NC cells are more epithelial while magenta star-shaped NC cells are more mesenchymal. Top and bottom rows shows lateral views and dorsal views, respectively. Orientations and structures are indicated on the figure. Ot. ves., otic vesicle.
FIGURE 2. Neural crest “mixotaxis.†(a) The classical view of cephalic NC cell directed cell migration in Xenopus laevis. NC cells become motile via EMT and exhibit a collective behavior [collective cell migration (CCM)] due to a balance between dispersion (CIL) and mutual attraction (or co-attraction, CoA). Placodes, located in the lateralectoderm, produce CXCL12, a well-known chemoattractant. NC cells express the main CXCL12 receptor, Cxcr4. NC are migrating toward latero-ventral territories due to CXCL12-dependent chemotaxis. (b) The current view of cephalic NC cell directed cell migration in Xenopus laevis in which CXCL12, by promoting cell-matrix adhesion, contributes to defining permissive areas for cell migration in the context of a biased distribution of topological features. These include chemical and physical cues and requires a minimal stiffness of the surrounding tissue for cell migration to proceed. The main difference with the classical view is that precise and biased spatial distribution of secreted molecules is dispensable. (c) A speculative view of what the actual control of cephalic NC cell directed cell migration in Xenopus laevis might look like with the inclusion of additional features such as a hypothetical graded distribution of stiffnesses (Durotaxis) and electric fields (Galvanotaxis) at tissue scale as well as iterative biases in topography at cellular and subcellular scales (Ratchetaxis). While most of these features can be experimentally disentangled under controlled ex vivo experiments, none of these cues relies on a specific set of molecular sensors and effectors but rather share downstream signal transduction machineries leading to cell adhesion and polarity. Therefore, in vivo, each input (e.g., chemical, mechanical, electrical) is likely to extensively feed into the others leading to the exciting idea that, in their native environment, NC cells may achieve directed migration by performing a sort of “mixotaxis.†See main text for details.
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