Prof. Dr. Sebastian Arnold (CIBSS AI), Institute of Experimental and Clinical Pharmacology and Toxicology (Faculty of Medicine), University of Freiburg
Cell lineage specification of the first strictly embryonic cell types is orchestrated by extracellular signals that instruct (primed) pluripotent cells during formation of the germ layers, ectoderm, mesoderm and endoderm. The first lineage separation diverges neuroectoderm from mesoderm and endoderm. While the mechanisms of signal transduction pathways were discovered decades ago, the precise details of signal integration that translates into formation of different cell fates still remain enigmatic. Open questions exist at the levels of cytoplasmic signal integration, cooperativity of signals with transcription control mechanisms, and epigenetic manifestation of cell lineage determination.
In this project we apply combinations of embryonic stem (ES) cell differentiation and embryonic analyses to study the earliest stages of lineage commitment during exit of pluripotency by induction of TGFβ-, BMP- and Wnt- signals. These inductive signals control mutual exclusive programs for neuroectoderm and meso-/endoderm lineage specification, involving early activities of Tbx-transcription factors, Eomes and Brachyury. We use 3D gastruloid models of embryoid bodies to define and study the crosstalk of signals and transcription factors in a 3D tissue over time. We apply genetics for the visualization of signaling readouts and for the experimental control of signals to decipher how lineage specification is spatiotemporally controlled within the organoids and in the developing embryo.
Publications resulting from the project:
Chimeric 3D-gastruloids – a versatile tool for studies of mammalian peri-gastrulation development
Alexandra E. Wehmeyer, Katrin M. Schüle, Alexandra Conrad, Chiara M. Schröder, Simone Probst, Sebastian J. Arnold
Spatiotemporal sequence of mesoderm and endoderm lineage segregation during mouse gastrulation.
Probst S, Sagar, Tosic J, Schwan C, Grün D, Arnold SJ.
Development. 2021; doi: 10.1242/dev.193789.
Eomes and Brachyury control pluripotency exit and germ-layer segregation by changing the chromatin state.
Tosic J, Kim GJ, Pavlovic M, Schröder CM, Mersiowsky SL, Barg M, Hofherr A, Probst S, Köttgen M, Hein L, Arnold SJ.
Nat Cell Biol. 2019; doi: 10.1038/s41556-019-0423-1.