Analysis and modulation of cell behaviours driving avian gastrulation

Abstract

Animal tissues acquire their final shape and size through the coordinated action of four fundamental cell behaviours: cell movement, division, change in cell shape and differentiation. The mechanisms that coordinate the spatiotemporal organisation of these cell behaviours and how they are integrated to generate the shapes in the developing body remain largely unresolved. Here I investigate how these cell behaviours drive morphogenesis during chick gastrulation. Vertebrate gastrulation consists of the internalisation of the mesendoderm to form a tri-laminar embryo from an epithelial sheet. In birds, large tissue flows to locate the mesendoderm precursors on the midline of the epiblast, where they undergo epithelial to mesenchymal transition and ingress, generating the primitive streak. In the first part of this thesis, I analyse how cell behaviours are balanced to achieve tissue homeostasis. The epiblast remains roughly constant in size during gastrulation through a combination of cell divisions, cell shape changes and the ingression of a previously unknown population of cells outside the primitive streak. Blocking the cell cycle through chemical inhibition suggests that cell ingression and division in the epiblast through the cell cycle. In the second part, I perform perturbations of developmental signalling pathways (VEGF, FGF, BMP, Wnt) that affect the patterning of cell behaviours. Strikingly, these perturbations modulate cell behaviours recapitulating some ancestral gastrulation modes such as the reptilian blastoporal canal, the fish germband and the amphibian blastopore in the chick embryo. Extensive analysis indicates that the domain of extending and shape of the mesoderm precursors and the cells’ ability to undergo EMT are the two main parameters controlling the mode of gastrulation. Alterations at the cell behaviour level through small changes in signalling can result in significant morphogenetic changes. These experiments show that it is possible to manipulate critical cell behaviours to synthesise alternative gastrulation modes within a single organism. The quantitative characterisation of how cell behaviours integrate signals to generate biological shapes is of primary importance for tissue engineering and the study of evolution.

Date of Award	2021
Original language	English
Sponsors	Biotechnology and Biological Sciences Research Council
Supervisor	Kees Weijer (Supervisor) & Rastko Sknepnek (Supervisor)