The emergence of multiple axes is an essential element in the establishment of the mammalian body plan. This process takes place shortly after implantation of the embryo within the uterus and relies on the activity of gene regulatory networks that coordinate transcription in space and time. Whereas genetic approaches have revealed important aspects of these processes1, a mechanistic understanding is hampered by the poor experimental accessibility of early post-implantation stages. Here we show that small aggregates of mouse embryonic stem cells (ESCs), when stimulated to undergo gastrulation-like events and elongation in vitro, can organize a post-occipital pattern of neural, mesodermal and endodermal derivatives that mimic embryonic spatial and temporal gene expression. The establishment of the three major body axes in these ‘gastruloids’2,3 suggests that the mechanisms involved are interdependent. Specifically, gastruloids display the hallmarks of axial gene regulatory systems as exemplified by the implementation of collinear Hox transcriptional patterns along an extending antero-posterior axis. These results reveal an unanticipated self-organizing capacity of aggregated ESCs and suggest that gastruloids could be used as a complementary system to study early developmental events in the mammalian embryo.
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We thank members of the Duboule, Lutolf and Martinez-Arias laboratories for sharing material and discussions, J. Deschamps for DNA clones, D. Trono for the Oct4::GFP iPSC line, the histology platform and the Gene Expression Core Facility (EPFL) as well as the genomics platform at Geneva University. This work was supported by funds from the BBSRC (No. BB/M023370/1 and BB/P003184/1 to A.M.A.), an NC3Rs David Sainsbury Fellowship (No. NC/P001467/1 to D.A.T.), an Engineering and Physical Sciences Research Council (EPSRC) Studentship (to P.B.-J.), a Company of Biologists Development Travelling Fellowship (DEVTF-151210 to P.B.-J.), a Newnham College Constance Work Junior Research Fellowship (to N.M.), the École Polytechnique Fédérale de Lausanne (D.D. and M.P.L.), the University of Geneva (D.D.), the Swiss National Research Fund (No. 310030B_138662 to D.D.) and the European Research Council grants ERC MOFDH (No. 250316 to A.M.A.), RegulHox (No 588029 to D.D.) and STEMCHIP (No 311422 to M.P.L.).
Nature thanks J. Briscoe and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Video 1: 3D rendering of 96 h AA gastruloid (corresponding to Fig. 1a 96 h AA). a. Gastruloids were produced from Gata6H2B-Venus fixed at 96h AA, stained for Gata6 (green), BRA (red) and SOX2 (white) and imaged by confocal microscopy as indicated in Materials and Methods. Each fluorescent channel is highlighted in turn for clarity. Hoechst was used to stain the nuclei. Data are representative of an experiment perfomed in parallel in seven independent biological replicates showing the same expression pattern.
Video 2: 3D rendering of 120 h AA gastruloid (corresponding to Fig. 1a 120 h AA). a. Gastruloids were produced from Gata6H2B-Venus fixed at 120 h AA, stained for Gata6 (green), BRA (red) and SOX2 (white) and imaged by confocal microscopy as indicated in Materials and Methods. Each fluorescent channel is highlighted in turn for clarity. Hoechst was used to stain the nuclei. Data are representative of an experiment perfomed in parallel in seven independent biological replicates showing the same expression pattern.