PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix
S Nahuel Villegas,
Michaela Rothová,
Martin E Barrios-Llerena,
Maria Pulina,
Anna-Katerina Hadjantonakis,
Thierry Le Bihan,
Sophie Astrof,
Joshua M Brickman
Affiliations
S Nahuel Villegas
Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; The Danish Stem Cell Center (DanStem), University of Copenhagen, Copenhagen, Denmark
Michaela Rothová
The Danish Stem Cell Center (DanStem), University of Copenhagen, Copenhagen, Denmark
Martin E Barrios-Llerena
Centre for Synthetic and Systems Biology (SynthSys), University of Edinburgh, Edinburgh, United Kingdom
Maria Pulina
Developmental Biology Program, Sloan-Kettering Institute, New York, United States; Center for Translational Medicine, Jefferson Medical College, Philadelphia, United States
Anna-Katerina Hadjantonakis
Developmental Biology Program, Sloan-Kettering Institute, New York, United States
Thierry Le Bihan
Centre for Synthetic and Systems Biology (SynthSys), University of Edinburgh, Edinburgh, United Kingdom
Sophie Astrof
Center for Translational Medicine, Jefferson Medical College, Philadelphia, United States
Joshua M Brickman
Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; The Danish Stem Cell Center (DanStem), University of Copenhagen, Copenhagen, Denmark
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.
