Analysis of the Signaling Networks Underlying Endoderm Development
Zusammenfassung der Projektergebnisse
Lung, liver and pancreas are derived from the endoderm germ layer and the formation and homeostasis of these organs is of great interest for medical research. Defining the key events of endoderm development will be beneficial in identifying targets in human disease and is fundamental in deriving differentiated cell types for replacement therapy. We generated a static embryo culture system to understand endoderm development on a cellular level by time-lapse imaging. This revealed that the Forkhead transcription factor a2 (Foxa2) is important for polarization and epithelialization in the endoderm epithelium. To understand how endoderm patterning translates into organ formation, we used cell-lineage tracing to follow the fate of distinct endoderm subpopulations. These results suggest that Foxa2 marks a bipotential progenitor cell population, which gives rise to a majority of cells in endoderm-derived organs, but also to cells in the cardiac lineage. In contrast, the SRY-related HMG box transcription factor Sox17 marks endoderm, vascular and hematopoietic progenitor cell populations. Conditional inactivation of β-catenin in these subpopulations has revealed a role of Wnt/βcatenin signaling in endoderm induction and subsequent patterning of the endoderm. To understand how Foxa2 regulates Spemann/Mangold organizer and endoderm formation, we carried out a screen to identify genes potentially regulated by Foxa2 and expressed in organizer cell population. We placed these genes in a Foxa2-dependent genetic regulatory network. Most importantly, we have identified two novel node genes (Pitchfork and Flattop) and have functionally analyzed them. Pitchfork regulates cilia disassembly and is most likely an evolutionary adaptation to Shh signaling. Flattop is a planar cell polarity effector molecule essential for basal body docking and/or orientation of cilia in the inner ear and lung epithelium. Both molecules provide an important entry point to understand ciliary disease of the endoderm-derived organs. On the basis of these findings an ERC starting grant was awarded.
Projektbezogene Publikationen (Auswahl)
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(2008). A mouse line expressing Foxa2-driven Cre recombinase in node, notochord, floorplate, and endoderm. Genesis 46(10): 515-522
Uetzmann L., Burtscher, I., and Lickert, H.
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(2008). Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation. Genes & Dev 22: 3349-3362
Egea, J., Erlacher, C., Montanez, E., Burtscher, I., Yamagishi, S., Heß, M., Hampel, F., Sanchez, R., Rodriguez-Manzaneque, M.T., Bösl, M.R., Fässler, R., Lickert, H., and Klein, R.
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(2008). MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol 10(3): 338-345
David, R., Brenner C., Stieber J., Schwarz F., Brunner S., Vollmer M., Mentele E., Müller-Höcker J., Kitajima S., Lickert, H., Rupp R., and Franz W.M.
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(2008). Microarray analysis of Foxa2 mutant mouse embryos identifies novel genes in the gastrula organizer and its derivates. BMC Genomics 9(1):511
Tamplin, O., Kinzel, D., Cox, B., Bell, C.E., Rossant, J., and Lickert, H.
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(2009). Foxa2 regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo. Development 136(6): 1029-1038
Burtscher, I. and Lickert, H.
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(2009). Generation of a mouse line expressing Sox17-driven Cre recombinase with specific activity in ateries. Genesis 47(7): 476-83
Liao W.Y., Uetzmann L., Burtscher, I., and Lickert, H.
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(2009). Sox17-2A-iCre: A knock-in mouse line expressing Cre recomibinase in endoderm and vascular endothelial cells. Genesis 47(9):603-10
Engert, S., Liao, W.Y., Burtscher, I., and Lickert, H.
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(2010). Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467(7311):59- 63
Nikoletopoulou, V., Lickert, H., Frade, J.M., Rencurel, C., Zhang, L., Bibel, M., and Barde, Y.A.
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(2010). Phenotypic annotation of the mouse X chromosome. Genome Research 20(8):1154-64
Cox, B., Vollmer, M., Tamplin, Lu, M., O., Biechele, S., Gertsenstein, M., Floss, T., Kuehn, R., Wurst, W., Lickert, H., Rossant, J.
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(2010). Pitchfork regulates primary cilia disassembly and left-right asymmetry. Dev Cell 19(1):66-77
Kinzel, D., Boldt, K., Davis, E., Burtscher, I., Truembach, D., Diplas, B., Attie-Bitach, T., Wurst, W., Katsanis, N., Ueffing, M., and Lickert, H.
