Cobo Rodriguez, I; (2014) Role of Complement C3 in gastrulation: a novel mechanism of ectoderm epiboly. Doctoral thesis , UCL (University College London).

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Abstract

The morphogenetic processes underlying gastrulation are driven through tightly localised cell rearrangements that occur in both ectodermal and mesodermal cells. While some of the cellular movement involved in the involution of the mesodermal cells have been studied in detail, and the movement of ectodermal cells have also been identified, we know very little about what regulates the movement of ectodermal cells during gastrulation. During gastrulation, the ectoderm suffers a dramatic expansion where an initial multilayered tissue becomes single-layered through a process called epiboly. During epiboly of the ectoderm, the superficial layer remains intact, whereas deep cells intercalate between each other, which accounts for an increase in the area of the tissue and the expansion of the superficial layer. However, the mechanism underlying radial intercalation of deep cells during epiboly remains to be unveiled. In zebrafish, radial intercalation of deep cells is thought to partially control the process of epiboly through which the embryo thins and wraps the underlying yolk. Mutants that impair epiboly have been known for some time and resulted from mutations of half-baked (which encodes for Ecadhrein). However, the role of Cdh1 in zebrafish epiboly has remained controversial and no detailed characterisation of the role Cdh1 in deep ectodermal cells of Xenopus gastrulation has been demonstrated. In this project, we study Xenopus epiboly in pursuing of a mechanism that could help us to understand how cell rearrangements are controlled throughout gastrulation. We have found that at in Xenopus gastrulae, the complement component C3a is expressed in the superficial layer superficial layer of the ectoderm, whereas its receptor (C3aR) is distinctly expressed in the deep layer. Complement factors are well characterized components of the immune response, and C3a has been described with chemoattractant activities by binding to it cognate receptor C3aR. We also found that in an in vitro assays deep layer cells move towards the superficial layer, showing for the first time chemotaxis of deep cells towards superficial ectoderm. Given the important role of C3a as a chemoattractant, we hypothesised that sensing cells from the deep layer of the ectoderm would be attracted to the C3a-expressing cells, superficiallayer, and that chemotactic movement contributes to radial intercalation of ectodermal cells. Indeed, in this thesis we demonstrate for the first time that cells from the deep layer of the ectoderm move towards the superficial layer in a process controlled by the anaphylotoxin complement component C3a. We also prove that C3a signalling through C3aR is indispensable for proper gastrulation as embryos lacking C3/C3aR in the ectoderm showed impaired epiboly and thicker ectoderm.

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