Analyse von Zell-Segregation und Zelltyp-spezifischem Verhalten während der frühen Differenzierung der Keimblätter in der Maus
Zusammenfassung der Projektergebnisse
The first cell lineage decision of pluripotent cells in the mammalian embryo segregates neuroectoderm (NE) from mesoderm and endoderm (ME) progenitor cells during the formation of the primary germ layers, being referred to as the gastrulation process. The project aimed at a precise embryonic description of the formation of the first cell lineages formed during gastrulation, anterior mesoderm (AM) and definitive endoderm (DE), and a molecular analysis of major transcriptional regulators involved in this process, namely Tbx factors Eomes and Brachyury. Our studies revealed the spatio-temporal pattern of AM and DE formation, by showing that AM forms in more proximal embryonic regions and temporaly precedes the formation of DE, as also demonstrated by timed genetic lineage-labeling. Both AM and DE lineages are descendents of Eomes-expressing cells in the epiblast. Single cell transcriptom (scRNA-seq) analyses demonstrate that Mesp1+ AM progenitors and Foxa2+ DE progenitors form immediately from non-lineage specified Eomes+ epiblast cells. Thus, the separation of AM and DE lineages is immediate and complete, so that the transient, non-lineage committed Eomes-expressing cells represents the last common bipotential mesendodermal progenitor in mouse. The second aim of this project focused on the functions of Tbx transcription factors Eomes and Brachyury during pluripotency exit and first lineage decision to NE and ME cell types. Out studies revealed that either of the two Tbx factors Eomes or Brachyury are essential for the specification of any ME cell type and the genetic deletion of both Tbx factors results in the prolonged maintenance of pluripotency and eventual differentiation to NE cell types. Chromatin analyses suggest that the main functions of Tbx factors is the establishment of accessible chromatin for the activation of ME gene enhancers, and the repression of pluripotency and NE genes by currently less understood mechanisms.
Projektbezogene Publikationen (Auswahl)
- (2019). Eomes and Brachyury control pluripotency exit and germ-layer segregation by changing the chromatin state. Nat Cell Biol 21, 1518-1531
Tosic, J., Kim, G.J., Pavlovic, M., Schroder, C.M., Mersiowsky, S.L., Barg, M., Hofherr, A., Probst, S., Kottgen, M., Hein, L., and Arnold, S.J.
(Siehe online unter https://doi.org/10.1038/s41556-019-0423-1) - (2021). Spatiotemporal sequence of early mesoderm and endoderm lineage segregation during mouse gastrulation. Development 148
Probst, S., Sagar, Tosic, J., Schwan, C., Grün, D., and Arnold, S.J.
(Siehe online unter https://doi.org/10.1038/s41598-018-20131-8)
