Dr Arno Muller
During tissue morphogenesis the individual cell architecture is profoundly reorganized to promote shape changes, to exchange neighbours or to become motile. The cellular events that occur during morphogenesis provide paradigms that advance our understanding of abnormal cell behaviour in human diseases.
We are using Drosophila as a model to study molecular mechanisms crucial for morphogenetic movements of epithelial cells. Cleavage of Drosophila embryos serves as a paradigm to study mechanisms required for the generation of polarized epithelial cells (Figure 1).
During gastrulation a subpopulation of epithelial cells, the presumptive mesoderm, undergoes an epithelial to mesenchymal transition (EMT) (Figure 2). We established that signalling through fibroblast-growth-factors is essential to trigger cell shape changes of mesoderm cells and identified two novel homologues of the FGF8/17/18 subfamily. Our focus of research is to understand how FGF-signalling controls complex cell rearrangements in the embryos and which molecular interactions lead to changes in cell adhesion and the cytoskeleton in the responding cells. A first handle of this problem is provided by our identification of the Rho guanine nucleotide exchange factor Pebble, the fly homologue of the human proto-oncogene ect2, as an essential component of this signalling pathway.
Figure 1- Confocal sections of an embryo during progression of cell formation. Plasma membrane (Neurotactin; green), adherens junctions (Armadillo/ß-catenin; red), nuclei (DNA; blue).
Figure 2- EMT during Drosophila gastrulation. Top row: cartoon of embryo cross sections (ectoderm red; mesoderm green). Middle row: mesoderm cells expressing a transgenic membrane marker (twi::CD2: red; Twist; green). Lower row: confocal optical sections. Phase 1 (‘tube’): mesoderm epithelial tube attached to ectoderm. Phase 2 (‘migration’) disintegration of epithelial tube and loss of epithelial polarity. The migrating cells form a leading edge and extend protrusions into the direction of their migration. Phase 3 (‘termination’) the mesoderm has adopted a monolayer configuration.
- Mariappa, D., Sauert, K., Marino, K., Turnock, D., Webster, R., van Aalten, D., Ferguson, M.A.J., Muller, H.-A.J. (2011) Protein O-GlcNAcylation is required for Fibroblast Growth Factor signaling in Drosophila. Science Signal, 4,ra89
- Van Uden, P., Kenneth, N.S., Webster, R., Muller, H.A., Mudie, S., Rocha, S. (2011) Evolutionary Conserved Regulation of HIF-1 beta by NF-kappa B. PLOS Genetics, 7(1): e1001285.
- Clark, I.B.N., Muha, V., Klingseisen, A., Leptin, M., Muller, H.-A.J. (2011) Fibroblast growth factor signaling controls successive cell behaviours during mesoderm layer formation in Drosophila. Development 138, 2705-2715.
- Winkbauer, R and Muller, HA (2011) Mesoderm layer formation in Xenopus and Drosophila gastrulation. Phys. Biol. 8,045001.
- Hain, D., Bettencourt, B., Okamura, K., Csorba, T., Meyer, W., Jin, J., Biggerstaff, J., Siomi, H., Hutvagner, G., Lai, E., Welte, M., Muller, HAJ. (2010) Natural variation of the amino-terminal glutamine-rich domain in Drosophila Argonaute 2 is not associated with developmental defects. PLoS ONE 5(12):e15264.
- Klingseisen, A., Clark, I.B. and Muller, H.-A.J. (2009) Differential and overlapping functions of two closely related Drosophila FGF8-like growth factors in mesoderm development. Development 136, 2393-2402.
- Kessler T. and Müller H.-A.J (2009). Cleavage of Armadillo/beta-catenin by the caspase DrICE in Drosophila apoptotic epithelial cells. BMC Dev Biol. 9, 15.
- van Impel, A., Schumacher, S., Draga, M., Herz, H.-M., Großhans, J. and Müller, H.-A.J. (2009). Regulation of the RacGTPase pathway by the multi-functional Rho GEF Pebble is essential for mesoderm migration in the Drosophila gastrula. Development 136, 813-822.
- Meyer, W.J., Schreiber, S., Guo, Y., Volkmann, T. Welte, M.A., and Müller, H.-A.J. (2006). Overlapping functions of Argonaute proteins in patterning and morphogenesis of Drosophila embryos. PLOS Genetics 2, 1224-1239.
- Großhans, J., Wenzl,C., Herz, H.-M., Bartoszewski, S., Schnorrer, F., Vogt, N., Schwarz, H., and Müller, H.-A.J. (2005). RhoGEF2 and the formin Dia control the formation of the furrow canal by directed actin assembly during Drosophila cellularisation. Development 132, 1009-1020.
- Schumacher, S., Gryzik, T., Tannebaum, S., and Müller, H.-A.J. (2004). The RhoGEF Pebble is required for cell shape changes during cell migration triggered by the Drosophila FGF receptor Heartless. Development 131, 2631-2640.
- Gryzik., T and Müller, H.A.J. (2004). FGF8-like1 and FGF8-like2 encode putative ligands of the FGF receptor Htl and are required for mesoderm migration in the Drosophila gastrula. Curr. Biology 14, 659-667.
- Wang, S.L., Hawkins C.J., Yoo, S.J., Müller, H.-A.J. and Hay, B.A. (1999). The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98, 453-463.
- Muha,V., Muller, H.A.J (2013). Functions and Mechanisms of Fibroblast Growth Factor (FGF) Signalling in Drosophila melanogaster. Int J Mol Sci. 14, 5920-37.