Molecular analysis of cell fate specification in mouse gastrulation
Final Report Abstract
During gastrulation the pluripotent cells of the epiblast are converted from a epithelial tissue into the different cell types of the primary germ layers. These cells are generated and placed in precise order within the embryo during gross morphogenetic rearrangements, thus establishing all primary tissue types and the basic embryonic body plan. Gastrulation was already widely studied and the majority of the molecular players were previously identified, however, our understanding of how cell specification is coordinated in this dynamic process by the interplay of transcriptional control, signalling events, and cellular behaviour itself remains incomplete. The research of the Emmy Noether group “Molecular control of cell lineage specification in mouse gastrulation” focused on the early events of gastrulation during the conversion from a pluripotent state to early-specified cell types of mesoderm and definitive endoderm (DE). It was shown that the T-box transcription factor Eomes plays a central and essential role for the generation of the two cell lineages of anterior mesoderm and definitive endoderm. Here, Eomes already acts at the initiating steps of specification and it is directly interconnected with proteins of the pluripotency maintaining network, Nanog and Oct4. Genome-wide ChIP approaches have shown that Eomes acts on top of the core transcriptional programmes for the cardiovascular and endoderm lineages. We could decipher how differential transcriptional responses downstream of Eomes are controlled by dynamically changing levels of Smad2/3-mediated TGFβ/Nodal signalling in the embryo and in differentiating ES cells. In contrast to Eomes/TGFβ-signallinghigh interactions that cooperatively promote allocation towards the DE lineage, the formation of cardiovascular progenitors requires only low levels of TGFβ/Smad2 activities and Eomes. This example of lineage commitment during gastrulation exemplifies how transcription factors function can be modulated by additional signals to exert different transcriptional responses. Future work aims for understanding in more detail how different cell types are discriminated and seperated during gastrulation. For example, mesoderm subtypes are early discriminated by different molecular programmes, that are at least partially characterized by the expression of different T-box proteins. Additionally, we will study how cell type specific behaviour during generation of the germ layers leads to the precise placement of cells according to their fate. Several novel genetic tools were generated that allow for visualization and genetic manipulating of cells during gastrulation.
Publications
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(2015) A Resource for the Transcriptional Signature of Bona Fide Trophoblast Stem Cells and Analysis of Their Embryonic Persistence. Stem cells international 2015, 218518
Kuales, Georg; Weiss, Matthias; Sedelmeier, Oliver; Pfeifer, Dietmar; Arnold, Sebastian J.
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(2011). Pluripotency Factors Regulate Definitive Endoderm Specification through Eomesodermin. Genes Dev 25, 238-250
Teo, A.K., Arnold, S.J., Trotter, M.W.B., Brown, S., Ang, L.T., Chng, Z., Robertson, E.J., Dunn, N.R., and Vallier, L.
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(2011). The T-box transcription factor Eomesodermin acts upstream of Mesp1 to specify cardiac mesoderm during mouse gastrulation. Nat Cell Biol 13(9), 1084-91
Costello, I., Pimeisl, I.M., Dräger, S., Bikoff, E.K., Robertson, E.J., and Arnold, S.J.
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(2013). Generation and characterization of a tamoxifen-inducible Eomes-CreER mouse line. Genesis 51(10), 725-733
Pimeisl, I., Tanriver, Y., Daza, R.A., Vauti, F., Hevner, R.F., Arnold, H.H., and Arnold, S.J.
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(2014). Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340-356
Klose, C.S.N., Flach, M., Möhle, L., Rogell, L., Hoyler, T., Ebert, Fabiunke, C., K., Pfeifer, D., Sexl, V., Souabni, A., Fonseca-Pereira, D., Domingues, R.G., Veiga-Fernandes, H., Arnold, S.J., Busslinger, M., Dunay, I.R., Tanriver, Y., and Diefenbach, A.
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(2014). Lsd1 controls differentiation onset and migration in trophoblast stem cells. Nat Commun 22; 5: 3174
Zhu, D., Hölz, S., Metzger, E., Pavlovic, M., Galgoczy, P., Baer, C., Moser, M., Metzger, D., Günther, T., Arnold, S.J. , and Schüle, R.
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(2015). Adult mice deficient in hippocampal neurogenesis exhibit less susceptibility to stress. Nat Commun. 29; 6: 8373
Tsai, C.-Y., Tsai, C.-Y., Arnold, S.J., and Huang, G.-J.
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(2015). Cyclin O (Ccno) functions in deuterosome-mediated centriole amplification of multiciliated cells. EMBO J 15;34(8):1078-89
Funk, M.C., Bera, A.N., Menchen, T., Kuales, G., Thriene, K., Lienkamp, S.S., Dengjel, J., Omran, H., Frank, M., and Arnold, S.J.
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(2016). Direct Reprogramming of Fibroblasts into Renal Tubular Epithelial Cells by Defined Transcription Factors. Nat Cell Biol 18(12):1269-1280
Kaminski, M.M., Tosic, J., Kresbach, C., Engel, H., Klockenbusch, J., Müller, A.-L., Pichler, R., Grahammer,F., Kretz, O., Huber, T.B., Walz, G., Arnold, S.J. , Lienkamp, S.S.
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(2016). Intermediate Progenitor Cohorts Differentially Generate Cortical Layers and Require Tbr2 for Timely Acquisition of Neuronal Subtype Identity. Cell Reports 28;16(1):92-105
Mihalas, A.B., Elsen, G.E., Bedogni, F., Daza, R.A., Ramos-Laguna, K.A., Arnold, S.J., Hevner, R.F.
