![]() ![]() False coloring indicates superficial cells (red), and the intercalation of outer-deep (light green) and inner-deep (dark-green) cells. (A) SEM images of blastocoel roof during epiboly in Xenopus embryos at stages 8, 10, and 11. Radial Intercalation Is Accompanied by Expression of C3 and C3aR during Xenopus Epiboly Several predictions of the model were tested in vivo, ex vivo, and in vitro, confirming the notion that short-range chemotaxis is required for ectoderm epiboly. ![]() We developed a computational model to test the hypothesis that RI is driven by deep cell (DC) chemotaxis toward superficial ectoderm cells (SCs). In immune cell homing, C3 is cleaved to produce C3a, a small anaphylatoxin peptide that binds to C3aR and triggers chemotaxis ( Leslie and Mayor, 2013). Using Xenopus laevis, the original model system to study RI, here we propose a mechanism for epiboly in which the rearrangement of ectodermal cells is driven by an unexpected activity of complement component C3, a factor normally associated with the immune system ( Ricklin et al., 2010, Leslie and Mayor, 2013). Although both cell-matrix and cell-cell adhesions are likely to be involved in some capacity, it is beyond doubt that other mechanisms are required to fully explain this process. A gradient of cell-cell adhesion molecules toward the superficial surface would drive ectodermal cells to move in the direction of the gradient, opposite to what the fibronectin hypothesis would predict ( Kane et al., 2005, Málaga-Trillo et al., 2009, Schepis et al., 2012). Studies of teleost epiboly propose cell sorting via differential cell adhesion as the driving force behind RI ( Kane et al., 2005, Málaga-Trillo et al., 2009, Schepis et al., 2012). However, this would not explain the intercalation of cells that are not in direct contact with the fibronectin. Studies of amphibian epiboly proposed that RI is driven by adhesion to a fibronectin matrix accumulated on the basal surface of the ectoderm allowing protrusive activity only at the fibronectin-free cell surfaces ( Marsden and DeSimone, 2001, Petridou et al., 2013, Sugrue and Hay, 1981). Two main mechanisms have been proposed so far to explain RI. Since then it has been recognized as a general morphogenetic process involved in a wide range of systems, including fish epiboly ( Warga and Kimmel, 1990), fly gastrulation ( Clark et al., 2011), amphibian and fish neural folding ( Kee et al., 2008), regeneration of hydra ( Kishimoto et al., 1996), and in mammalians during gastrulation ( Yen et al., 2009), gut development ( Yamada et al., 2010), and ear development ( Chen et al., 2002). RI was first described during the uniform expansion of the ectoderm in the animal pole region during amphibian gastrulation ( Keller, 1980). ![]() During epiboly, the number of cell layers in a multilayered epithelium is reduced by cell intercalation, a process called radial intercalation (RI). This study provides insight into the fundamental process of radial intercalation and could be applied to a wide range of morphogenetic events.Īcquiring shape and form in multicellular organisms involves deformation of epithelial sheets through bending (invagination), extension through narrowing (convergent extension), and expansion via thinning (epiboly). This mechanism is robust against fluctuations of chemoattractant levels and expression patterns and explains expansion during epiboly. We identify the chemoattractant as the complement component C3a, a factor normally linked with the immune system. The mechanism is explored by computational modeling and tested in vivo, ex vivo, and in vitro. This role of chemotaxis in tissue spreading and thinning is unlike its typical role associated with large-distance directional movement of cells. Using amphibian epiboly, the thinning and spreading of the animal hemisphere during gastrulation, here we provide evidence that radial intercalation is driven by chemotaxis of cells toward the external layer of the tissue. Radial intercalation is a fundamental process responsible for the thinning of multilayered tissues during large-scale morphogenesis however, its molecular mechanism has remained elusive. ![]()
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