Examplepictures of DNA-Structures

Suzanne Eaton - Developmental Cell Biology of Invertebrates

since 2015 Professor of Developmental Cell Biology of Invertebrates,TU-Dresden

since 2004 Senior group leader, MPI-CBG, Dresden

2000 - 2004 Group leader, MPI-CBG, Dresden

1997 - 2000 Staff Scientist, EMBL Heidelberg

1993 - 1997 Postdoctoral fellow, EMBL Heidelberg, Lab Kai Simons

1988 - 1993 Postdoctoral fellow, University of California at San Francisco, Lab Tom Kornberg

1988 Ph.D. Microbiology, University of California at Los Angeles

1981 - 1988 Sc.B. Biology, Brown University, Providence Rhode Island

Research focus

 

What controls tissue size and shape? It has long been clear that morphogen gradients emanating from organizer regions regulate the amount and orientation of growth and couple it to morphogenesis and tissue patterning. But how they do so is not understood. Ultimately, the activity of these pathways must direct the metabolic switches that regulate growth, and the mechanical forces exerted by cells as they divide, change shape and rearrange themselves. Our goal is to understand how morphogens regulate patterns of cellular metabolic and mechanical properties, and how tissue size and shape emerges from the collective interactions of these constituent cells. We approach the problem with cell biological, biochemical, biophysical, and quantitative imaging tools, and work with physicists to develop multiscale models that explore the logic of development.

 

Research Results

 

Epithelial morphogenesis in the wing of Drosophila

 


We focus on the Drosophila wing to understand size and shape control. Wing shape depends on growth orientation during larval stages and on later morphogenetic movements occurring in the pupa. To study cellular events underlying oriented growth and morphogenesis, we developed imaging and segmentation methods that allow us to track every cell in the wing and analysis methods to quantify contributions of cell division, cell rearrangement and cell deformation to tissue size and shape changes [1-4]. These methods have revealed the cellular basis of larval wing growth and pupal wing morphogenesis, and allow us to analyse the effects of mechanical and genetic perturbations in unprecedented detail (Dye et al., submitted) and [5]. To image growth of the larval wing disc, we had to solve the problem of how to maintain normal growth in culture. We discovered that the steroid hormone ecdysone is required to maintain morphogen expression and growth, both in culture andin vivo.Analyzing cell dynamics in explanted discs revealed that the orientation of cell division cannot quantitatively account for growth anisotropy in the larval wing. Cell rearrangements and shape changes that block tissue expansion orthogonal to the growth axis contribute equally to oriented tissue growth (Dye et al., submitted). Wing shape is refined during pupal morphogenesis as the wing hinge contracts and the more distal wing blade elongates in the proximal distal axis and narrows in the anterior-posterior axis [6]. Our analysis quantitatively accounts for shape change in the wing blade on the basis of cell dynamics throughout the blade. Analyzing mutant and mechanical perturbed wings showed that the cell dynamics that shape the wing blade result from an interplay of active, autonomously controlled cell behaviour, and cellular response to tissue stresses that emerge during morphogenesis – in part as a consequence of hinge contraction. This generates tissue stress because of patterned connections to an apical extracellular matrix. These connections, and the interplay between active and stress-induced cellular events, quantitatively reproduce wing shape changes in a theoretical model [5]. How do morphogens control the patterns of cell dynamics that underlie wing growth and morphogenesis? These patterns of cell dynamics are strikingly oriented within the plane of the epithelium, suggesting a key role for planar cell polarity (PCP) systems in guiding these processes. Morphogen signalling orients global patterns of two planar cell polarity systems, Fat PCP and Core PCP[7]. Proteins in both pathways localize to adherens junctions and form distinct asymmetric intracellularly polarized complexes that couple the polarity of adjacent cells. The intracellular orientation of these complexes is organized in global patterns that change dynamically during growth and morphogenesis [7, 8]. During growth, Fat and Core PCP domains are present on the same cell boundaries and their global polarity patterns are indistinguishable. Their patterns become uncoupled during pupal tissue flows as the wing changes shape, so that Core PCP domains face distally and Fat PCP domains orient orthogonal to them. At this stage, distally oriented Core PCP domains guide the distally-oriented outgrowth of wing hairs. Later, the Fat and Core PCP domains undergo another global reorganization and align with each other in a new pattern that guides formation of cuticular ridges [8]. We are now investigating the interplay between these PCP systems and epithelial morphogenesis. While it is clear that oriented tissue flows can influence global PCP patterns [6], we also expect that the distinct cell biological and biophysical properties of cell boundaries harbouring different combinations of PCP domains will feed back on the morphogenetic process itself [9].


Metabolism and the cell biology of Hedgehog signalling

 


Metabolism has a key role in regulating growth. Organismal growth is limited by nutritional conditions, but even small animals that emerge under nutritional restriction or elevated temperature are normally patterned. How do temperature and nutrition appropriately influence patterns of morphogen signalling so that tissue pattern scales with size? Conversely, the growth promoting processes driven by morphogen signalling likely involve changes in cell metabolism. We would like to understand this interplay, particularly focusing on Hedgehog family morphogens. Hedgehog proteins can be covalently modified by acyl groups at the N-terminus and by cholesterol at the C-terminus. A key finding was that double lipid-modified Hedgehog proteins are released from cells on circulating lipoproteins, providing a clue to how systemic metabolism could influence morphogen activity. We discovered that lipoproteins influence Hh signalling both at the level of ligand secretion and downstream signalling components. Lipoproteins increase release of Hh ligands, but also contain lipids that inhibit signalling. Lipoprotein-associated Hh signals by blocking utilization of these lipids for pathway repression. The inhibitory lipids are endocannabinoids, and act by binding and inhibiting Smoothened, the 7-pass transmembrane protein that transmits the Hh signal. Phytocannabinoids are also potent inhibitors. These mechanisms are conserved from flies to man. While a large fraction of Hedgehog is covalently modified by cholesterol at its C-terminus, we discovered a novel release form that is not sterol modified and does not associate with lipoproteins. Lipoprotein-associated Hh and non-sterol modified Hh influence the pathway in different ways, and signal synergistically [10, 11]. The mechanisms that control the balance of these two forms will be key to understanding how Hedgehog regulates growth and patterning and are a major interest in the lab now.


Drosophila lipidomics and temperature acclimation

 

To effectively study the interface between Hh signalling and lipid metabolism in Drosophila requires an understanding of lipid metabolism in this organism. We therefore described the tissue sources and inter-organ trafficking pathways of the three major Drosophila lipoproteins [13]. We studied their lipid cargo, and how lipoprotein-mediated lipid delivery influences tissue lipid composition. We discovered a sterol-dependent growth checkpoint, and showed that tissue lipid composition is directly influenced by diet – animals fed on yeast and plants have different tissue lipid compositions that reflect the fatty acids in the food source [14, 15]. In addition to providing an organismal context in which to study Hh signalling, these studies unexpectedly led us to an understanding of how flies adjust their physiologic to survive and develop at different temperatures. Flies fed yeast and plant food have different viable temperature ranges that depend on dietary lipid composition. Flies prefer to feed on plants at low temperature. Plant lipids promote membrane fluidity, allowing animals to develop at low temperatures and survive freezing. In contrast, flies prefer to feed on yeast at high temperature. Yeast lipids increase survival at high temperatures by promoting the release of insulin-like peptides and speeding development [16].


A Drosophila Rab library

 


Over the last decade, cell and developmental biology have almost completely merged. It is impossible to solve problems in developmental biology without understanding how cells organize themselves and signal to each other. Conversely, the necessity of studying cell biological processes in vivo rather than in tissue culture is becoming increasingly obvious. We developed a comprehensive genetic resource that represents a new entry point into the study of membrane trafficking in vivo: the Drosophila YRab library. The Rab family of small GTPases control specific steps in intracellular membrane trafficking – Rabs that regulate the secretory and endocytic pathways have been well studied in tissue culture, but there are many additional family members whose functions are completely unknown. We have used homologous recombination to fuse YFP to the N-terminus of each of the 27 Drosophila Rabs in its endogenous chromosomal locus. These lines provide powerful new tools for both Rab compartment visualization and functional analyses. Endogenous tissue expression and subcellular localization can be visualized in the absence of over-expression artifacts. Targeting the YFP tag allows efficient, specific and controllable knock-down of Rab function. We examined subcellular localization of all 27 Drosophila Rabs in 6 different tissues comprising over 23 cell types. Original image data is available in an annotated, searchable and downloadable database. We exploited this comprehensive dataset to address several basic questions in Rab evolution and cell polarization [17].

References

  1. Popovic, M., Nandi, A., Merkel, M., Etournay, R., Eaton, S., Julicher, F., and Salbreux, G. (2017). Active Dynamics of tissue shear flow. New Journal of Physics 19, 1-19.
  2. Merkel, M., Etournay, R., Popovic, M., Salbreux, G., Eaton, S., and Julicher, F. (2017). Triangles bridge the scales: Quantifying cellular contributions to tissue deformation. Physical Review E 95, 032401-032424.
  3. Etournay, R., Merkel, M., Popovic, M., Brandl, H., Dye, N.A., Aigouy, B., Salbreux, G., Eaton, S., and Julicher, F. (2016). TissueMiner: A multiscale analysis toolkit to quantify how cellular processes create tissue dynamics. eLife 5.
  4. Aigouy, B., Umetsu, D., and Eaton, S. (2016). Segmentation and Quantitative Analysis of Epithelial Tissues. Methods Mol Biol 1478, 227-239.
  5. Etournay, R., Popovic, M., Merkel, M., Nandi, A., Blasse, C., Aigouy, B., Brandl, H., Myers, G., Salbreux, G., Julicher, F., et al. (2015). Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing. eLife 4, e07090.
  6. Aigouy, B., Farhadifar, R., Staple, D.B., Sagner, A., Roper, J.C., Julicher, F., and Eaton, S. (2010). Cell flow reorients the axis of planar polarity in the wing epithelium of Drosophila. Cell 142, 773-786.
  7. Sagner, A., Merkel, M., Aigouy, B., Gaebel, J., Brankatschk, M., Julicher, F., and Eaton, S. (2012). Establishment of global patterns of planar polarity during growth of the Drosophila wing epithelium. Curr Biol 22, 1296-1301.
  8. Merkel, M., Sagner, A., Gruber, F.S., Etournay, R., Blasse, C., Myers, E., Eaton, S., and Julicher, F. (2014). The balance of prickle/spiny-legs isoforms controls the amount of coupling between core and fat PCP systems. Curr Biol 24, 2111-2123.
  9. Eaton, S., and Julicher, F. (2017). Emergence of tissue shape changes from collective cell behaviors. Seminars in Cell and Developmental Biology in press.
  10. Palm, W., Swierczynska, M.M., Kumari, V., Ehrhart-Bornstein, M., Bornstein, S.R., and Eaton, S. (2013). Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals. PLoS Biol 11, e1001505.
  11. Rodenfels, J., Lavrynenko, O., Ayciriex, S., Sampaio, J.L., Carvalho, M., Shevchenko, A., and Eaton, S. (2014). Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development. Genes Dev 28, 2636-2651.
  12. Swierczynska, M.M., Mateska, I., Peitzsch, M., Bornstein, S.R., Chavakis, T., Eisenhofer, G., Lamounier-Zepter, V., and Eaton, S. (2015). Changes in morphology and function of adrenal cortex in mice fed a high-fat diet. Int J Obes (Lond) 39, 321-330.
  13. Palm, W., Sampaio, J.L., Brankatschk, M., Carvalho, M., Mahmoud, A., Shevchenko, A., and Eaton, S. (2012). Lipoproteins in Drosophila melanogaster--assembly, function, and influence on tissue lipid composition. PLoS Genet 8, e1002828.
  14. Carvalho, M., Sampaio, J.L., Palm, W., Brankatschk, M., Eaton, S., and Shevchenko, A. (2012). Effects of diet and development on the Drosophila lipidome. Mol Syst Biol 8, 600.
  15. Carvalho, M., Schwudke, D., Sampaio, J.L., Palm, W., Riezman, I., Dey, G., Gupta, G.D., Mayor, S., Riezman, H., Shevchenko, A., et al. (2010). Survival strategies of a sterol auxotroph. Development 137, 3675-3685.
  16. Brankatschk, M., Gutmann, T., Grzybek, M., Brankatschk, B., Coskun, U., and Eaton, S. (2016). A temperature dependent shift in dietary preference alters the viable temperature range of Drosophila. BioRXiv.
  17. Dunst, S., Kazimiers, T., von Zadow, F., Jambor, H., Sagner, A., Brankatschk, B., Mahmoud, A., Spannl, S., Tomancak, P., Eaton, S., et al. (2015). Endogenously tagged rab proteins: a resource to study membrane trafficking in Drosophila. Dev Cell 33, 351-365.

Future prospects and goals

 

Over the longer term, we want to understand the effects of morphogen signaling on both cell mechanics and cell metabolism, and how this interplay changes as tissues approach their final size.

 

 

Selected publications

  1. Merkel, M., et al., Triangles bridge the scales: Quantifying cellular contributions to tissue deformation. Physical Review E 2017. 95(3): p. 032401-032424.
  2. Etournay, R., et al.,TissueMiner: A multiscale analysis toolkit to quantify how cellular processes create tissue dynamics.Elife, 2016.
  3. Brankatschk, M., et al.,A temperature dependent shift in dietary preference alters the viable temperature range of Drosophila. BioRXiv, 2016.
  4. Khaliullina,H., et al.,Endocannabinoids are conserved inhibitors of the Hedgehog pathway. Proc Natl Acad Sci U S A, 2015.112(11): p. 3415-20.
  5. Etournay, R., et al.,Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing. Elife, 2015.: p. e07090.
  6. Dunst,S., et al., Endogenously tagged rab proteins: a resource to study membrane trafficking in Drosophila. Dev Cell, 2015.33(3): p. 351-65.
  7. Rodenfels, J., et al., Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development. Genes Dev, 2014. 28 (23): p. 2636-51.
  8. Merkel, M., et al., The balance of prickle/spiny-legs isoforms controls the amount of coupling between core and fat PCP systems. Curr Biol, 2014. 24(18):p. 2111-23.
  9. Brankatschk, M., et al., Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling. Elife, 2014. 3.
  10. Palm, W., et al., Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals. PLoS Biol, 2013. 11(3): p. e1001505.

Further Links

Group Webpage MPI-CBG

 

Group Members

You can find a list of current group members here.

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