Further Development 11.2: How Do Deeper Ectodermal Cells "Know" to Intercalate Toward the Surface Ectoderm?

Amphibians and Fish

Similar to the way we might use street signs (or a smartphone map app) to find our way around a city, the deeper ectodermal cells might be following some sort of guidance information for their directional movement. Such mapping mechanisms have been well characterized in other contexts, such as the use of complement component for the trafficking associated with immune cell homing (Leslie and Mayor 2013). Could a guidance mechanism such as cell homing, traditionally thought of as long-range guidance, also be employed to guide deep ectodermal cells the very short distance to surface layers during radial intercalation? Surprisingly, complement component 3a (C3a) is expressed by cells of the superficial epithelial monolayer but not by the deeper multilayers. The Mayor laboratory recently took a dual in silico and in vivo approach to model and experimentally test the role of C3a during Xenopus epiboly (Szabó et al. 2016). Knockdown of C3a with antisense morpholinos prevents radial intercalation, and the ectoderm layers fail to thin (Figure 1A). In addition, ectopic misexpression of C3a with the application of a C3a-expressing cell graft results in the dramatic accumulation of ectodermal cells under the graft. Therefore, in both computer simulations and in the embryo, C3a functions as a short-range chemoattractant to guide the radial intercalation movements of cells in the deep ectodermal layers (Figure 1B).

Figure 1 Complement component 3a (C3a) from the superficial epithelial monolayer attracts the movement of underlying deep cells during epiboly. (A) The top two rows show computer simulations of cell configurations (top row) and corresponding chemoattractant levels (second row) at the end of epiboly for control (Chem+) and for loss (Chem–) or localized gain (Chem+Graft) of C3a chemotaxis. The bottom row of images shows the in vivo experimental validation of the computer simulations through morpholino knockdown of C3a (C3Mo; control, CoMo) and the localized misexpression of C3a by a graft (C3a Graft). The position of labeled deep cells (membranes, green; nuclei, red) in these cross sections of the blastocoel roof was measured to demonstrate changes in ectoderm thickness (shown by white bars). (B) Model of C3a chemoattractant function during radial intercalation of the deep layers. C3aR+ deep cells interpret the C3a ligand secreted from the superficial cells as an attractant, which guides deep cells to migrate radially and outward, forcing the superficial layer to thin and expand. C3a, protein acting as a chemoattractant; C3aR, receptor for C3a. (B after A. Szabó et al. 2016. Dev Cell 37: 213–225.)

 

Literature Cited

Leslie, J. D. and R. Mayor. 2013. Complement in animal development: Unexpected roles of a highly conserved pathway. Semin. Immunol. 25: 39–46.

Szabó, A., I. Cobo, S. Omara, S. McLachlan, R. Keller and R. Mayor. 2016. The molecular basis of radial intercalation during tissue spreading in early development. Dev. Cell 37: 213–225.

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