Abstract
During embryonic development signalling pathways act repeatedly in different contexts to pattern the emerging germ layers. Understanding how these different responses are regulated is a central question for developmental biology. In this study, we used mouse embryonic stem cell (mESC) differentiation to uncover a new mechanism for PI3K signalling that is required for endoderm specification. We found that PI3K signalling promotes the transition from naïve endoderm precursors into committed anterior endoderm. PI3K promoted commitment via an atypical activity that delimited epithelial-to-mesenchymal transition (EMT). Akt1 transduced this activity via modifications to the extracellular matrix (ECM) and appropriate ECM could itself induce anterior endodermal identity in the absence of PI3K signalling. PI3K/Akt1-modified ECM contained low levels of Fibronectin (Fn1) and we found that Fn1 dose was key to specifying anterior endodermal identity in vivo and in vitro. Thus, localized PI3K activity affects ECM composition and ECM in turn patterns the endoderm.
DOI:
http://dx.doi.org/10.7554/eLife.00806.001
From conception to birth, a single fertilised egg will multiply into trillions of cells, with each cell becoming one of the 200 or so different types of cell that are found in the human body. The development of an embryo is complex and dynamic, with cells giving up their ability to become any cell type and committing to becoming a specific cell type within a given tissue. At the same time, different groups of cells migrate to the appropriate locations within the developing embryo. Although it is challenging to decipher the roles of the individual signalling pathways that control an embryo’s development, several important components have been found.
Fibroblast growth factor (FGF) is a protein that regulates the formation of the endoderm: this is the innermost of the three layers of cells that form in the early embryo, and it gives rise to internal organs such as the gut, liver and pancreas. As well as ‘telling’ cells to become the front part, or anterior, of the endoderm, FGF also controls the migration of these cells within the embryo. However, uncoupling these two roles has been a major challenge, and the molecular mechanisms behind them are unclear.
Now, Villegas et al. have discovered that FGF activates a signalling cascade involving two enzymes called PI3K and Akt1. In lab-grown embryonic stem cells—cells that can be coaxed to become any of the cell types formed during development—this signalling cascade is essential for FGF to trigger differentiation of the cell types found in the anterior endoderm. The PI3K/Akt1 signalling cascade achieves this by reducing the level of a protein called fibronectin in the ‘extracellular matrix’ that surrounds the cells. This low level of fibronectin will in turn induce cells to stick together in an organized layer; and this rearrangement of cell-cell and cell-matrix interactions appears linked to triggering the differentiation of anterior endoderm cell types.
Villegas et al. showed that the PI3K/Akt1 pathway was also essential for endoderm formation in living mouse embryos. As a normal embryo develops, the anterior endoderm cells move into a ‘groove’ at the front the embryo, where the level of fibronectin is lower than it is at the posterior end of the embryo.
These findings highlight the importance of the extracellular matrix in the regulation of embryonic development, and should assist in the effort to turn lab-grown stem cells into the useful cell types found in internal organs.
DOI:
http://dx.doi.org/10.7554/eLife.00806.002