title: PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix.
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.
authors.affiliation: Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: S Nahuel
authors.initials: SN
authors.lastname: Villegas
authors.forename: Michaela
authors.initials: M
authors.lastname: Rothová
authors.forename: Martin E
authors.initials: ME
authors.lastname: Barrios-Llerena
authors.forename: Maria
authors.initials: M
authors.lastname: Pulina
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.forename: Thierry
authors.initials: T
authors.lastname: Le Bihan
authors.forename: Sophie
authors.initials: S
authors.lastname: Astrof
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Brickman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D018920:Coculture Techniques; D046149:Embryo Culture Techniques; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009024:Morphogenesis; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D005353:Fibronectins; D005346:Fibroblast Growth Factors; D058539:Phosphatidylinositol 3-Kinase; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Fibronectin; PI3K/Akt1; endoderm; extracellular matrix; foregut; proteomics