The effects of BMP4 on different in vitro models for mouse gastrulation and neural induction

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Pérez Valle, Helena  ORCID logo

Bone morphogenetic protein 4 (BMP4) is a signaling protein involved in several key developmental processes, including gastrulation and neural induction. Gastrulation is an event that changes the topology of the embryo, organising a single layer or ball of cells into the three primordial germ layers: the mesoderm, endoderm and ectoderm. In the mouse embryo, gastrulation starts with a group of asymmetrically positioned cells expressing a group of genes that include T/Brachyury. These cells undergo a directed epithelial to mesenchymal transition (EMT) that gives rise to the Primitive Streak. BMP4 mutant mice fail to form a Primitive Streak or do so defectively. Neural induction is the process that gives rise to the brain, by ensuring that embryonic cells become neural tissue rather than mesoderm, endoderm, or other types of ectoderm. Inhibition of BMP4 signaling is required for neural induction to take place. Gastruloids are a 3D culture model that does not require BMP4 to undergo gastrulation-like events. This thesis describes the effects of BMP4 on gastruloids and on a 2D adherent cell culture model for gastrulation, demonstrating the interactions between BMP4, Nodal, Wnt, and Brachyury. It also shows that BMP4, although not expressed in gastruloids, can enhance certain phenotypes associated with gastrulation when added to the gastruloid culture medium. The results shown in this part of the thesis support the hypothesis that BMP4 acts as a permissive molecule, increasing the chances of establishing the Primitive Streak in the correct region of the embryo. The development of a new 3D culture model for neural induction is also described, as are the effects of BMP4 on this model. This newly-developed model for neural induction is used to demonstrate that BMP4 inhibits neural induction and that a BMP4 antagonist (Noggin) enhances neural differentiation in this system.

Martínez Arias, Alfonso
BMP4, gastrulation, neural induction, gastruloids, development, mouse, embryonic stem cells, mESCs, in vitro culture models, Nodal, Wnt, mEpiSCs
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
The BBSRC funded my PhD through their Cambridge University Biology Doctoral Training Programme (Cambridge Biosciences BBSRC DTP).