A15 - Gilmour

The study of neural development is normally subdivided into two broad fields. Neural patterning addresses the inductive interactions that lead to different neuronal fates. Neural morphogenesis studies the coordinated cell shape changes and movements that shape the nervous system, with the majority of neurons taking up their final location through a collective migration process. While neuronal differentiation and migration are usually studied in isolation, these two events must be somehow coupled as cells always adopt a fate that is appropriate for their final location. How this coupling is achieved is unknown but it is reasonable to suggest that physical cell-cell interactions may inform cells of their positioning within these complex moving groups. The primordium of the fish lateral line system is a promising model system for addressing the relationship between cell migration and fate. It is a migrating placode that becomes subdivided into rosette-like mechanosensory organs en route. The sensory hair cells that develop at the centre of the rosette are specified while the primordium is still migrating, as revealed by the transcription of the proneural gene atonal 1a and its upstream activator fgf-10. Surprisingly, expression analysis performed on fixed specimens reveals that the restricted expression of these genes to individual hair cells occurs only after the rosettes have assembled. These and other data suggest that the mechanics of sensory organ assembly may help select which cells adopt a neuronal fate.

The aim of this proposal is to exploit the experimental and imaging strengths of the lateral line to address how the expression of genes controlling neuronal cell fate, FGF-10 and atonal 1a, is coupled to cell movement and shape changes within moving groups. We will generate transgenic embryos where the dynamic expression of these determinants can be quantified across the migrating primordium. Segmentation of time-lapse data will allow us to precisely correlate changes in the patterned expression of these genes with cell geometry. Combining the reporter fish with perturbation experiments where the tissue is stretched or compressed, using mutants and laser nanosurgery, we will test the role of tissue mechanics in the regulating neuronal specification in vivo. We will directly test the role of the actinomyosin system in mediating mechanosensation in this in vivo context, by inhibiting or increasing myosin II activitation in individual cells within the moving group.

Die Mehrheit aller Neurone findet ihren endgültigen Bestimmungsort durch zielgerichtete Zellwanderung. Die Mechanismen, die sicherstellen, daß diese wandernden Nervenzellen so differenzieren, wie es für ihre Zielposition erforderlich ist, sind weitestgehend unbekannt. Es ist allerdings sehr wahrscheinlich, daß physikalische Zell-Zell Interaktionen eine wichtige Rolle spielen. Während der Entwicklung des Seitenlinienorgans im Zebrafischembryo enstehen eine Reihe von Haarzellorganen, deren Organisation und Differenzierung innerhalb eines migrierenden Primordiums beginnt. Unsere vorläufigen Ergebnisse weisen darauf hin, daß die Spezifizierung der Haarsinneszellen im Zentrum dieser Organe dynamisch auf mechanische Reize im Gewebe reagiert. Unser Ziel ist es, die Vorteile des Zebrafischsystems, wie einfache Manipulierbarkeit und die hervorragende Eignung für in vivo Mikroskopie, zu nutzen um verstehen zu können, wie die Expression neuraler Schlüsselregulatoren, sowie Form und Position von Zellen innerhalb des wandernden Gewebes miteinander gekoppelt sind.

Own project-related publications

Campos-Ortega, J. A. (1997) Asymmetic division: dynastic intricacies of neuroblast division. Curr Biol 7: R726-728

Doe, C. Q., and Skeath, J. B. (1996) Neurogenesis in the insect central nervous system. Curr Opin Neurobiol 6: 18-24

Losick, R., and Desplan, C. (2008) Stochasticity and cell fate. Science 320: 65-68

Brown, K. E., Baonza, A., and Freeman, M. (2006) Epithelial cell adhesion in the developing Drosophila retina is regulated by Atonal and the EGF receptor pathway. Dev Biol 300: 710-721

Corrigall, D., Walther, R. F., Rodriguez, L., Fichelson, P., and Pichaud, F. (2007) Hedgehog signaling is a principal inducer of Myosin-II-driven cell ingression in Drosophila epithelia. Dev Cell 13: 730-742

Escudero, L. M., Bischoff, M., and Freeman, M. (2007) Myosin II regulates complex cellular arrangement and epithelial architecture in Drosophila. Dev Cell 13: 717-729

Discher, D. E., Janmey, P., and Wang, Y. L. (2005) Tissue cells feel and respond to the stiffness of their substrate. Science 310: 1139-1143

Engler, A. J., Sen, S., Sweeney, H. L., and Discher, D. E. (2006) Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689

Dambly-Chaudière, C., Sapède, D., Soubiran, F., Decorde, K., Gompel, N., and Ghysen, A. (2004) The lateral line of zebrafish: a model system for the analysis of morphogenesis and neural development in vertebrates. Biol Cell 95: 579-587

Ghysen, A., and Dambly-Chaudiere, C. (2007) The lateral line microcosmos. Genes Dev 21: 2118-2130

Itoh, M., and Chitnis, A. B. (2001) Expression of proneural and neurogenic genes in the zebrafish lateral line primordium correlates with selection of hair cell fate in neuromasts. Mech Dev 102: 263-266

Sarrazin, A. F., Villablanca, E. J., Nuñez, V. A., Sandoval, P. C., Ghysen, A., and Allende, M. L. (2006) Proneural gene requirement for hair cell differentiation in the zebrafish lateral line. Dev Biol 295: 534-545

*Gilmour, D., Knaut, H., Maischein, H. M., and Nusslein-Volhard, C. (2004) Towing of sensory axons by their migrating target cells in vivo. Nat Neurosci 7: 491-492

*Gilmour, D. T., Maischein, H. M., and Nusslein-Volhard, C. (2002) Migration and function of a glial subtype in the vertebrate peripheral nervous system. Neuron 34: 577-588

*Haas, P., and Gilmour, D. (2006) Chemokine signaling mediates self-organizing tissue migration in the zebrafish lateral line. Dev Cell 10: 673-680

*Valentin, G., Haas, P., and Gilmour, D. (2007) The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b. Curr Biol 17: 1026-1031

Colombelli, J., Pepperkok, R., Stelzer, E. H., and Reynaud, E. G. (2006) Laser nanosurgery in cell biology. Med Sci (Paris) 22: 651-658

Colombelli, J., Reynaud, E. G., and Stelzer, E. H. (2007) Investigating relaxation processes in cells and developing organisms: from cell ablation to cytoskeleton nanosurgery. Methods Cell Biol 82: 267-291

*Haas, P., Lecaudey, V., Colombelli, J., Stelzer, E. H., and Gilmour, D. (2008) Mechanical Regluation of Directional Migration and Organ Assembly in the Zebrafish lateral line. In preparation.

Roehl, H., and Nüsslein-Volhard, C. (2001) Zebrafish pea3 and erm are general targets of FGF8 signaling. Curr Biol 11: 503-507

Akai, J., Halley, P. A., and Storey, K. G. (2005) FGF-dependent Notch signaling maintains the spinal cord stem zone. Genes Dev 19: 2877-2887

Henrique, D., Tyler, D., Kintner, C., Heath, J. K., Lewis, J. H., Ish-Horowicz, D., and Storey, K. G. (1997) cash4, a novel achaete-scute homolog induced by Hensen's node during generation of the posterior nervous system. Genes Dev 11: 603-615

Martinez-Morales, J. R., Del Bene, F., Nica, G., Hammerschmidt, M., Bovolenta, P., and Wittbrodt, J. (2005) Differentiation of the vertebrate retina is coordinated by an FGF signaling center. Dev Cell 8: 565-574

Cakan, G., Lecaudey, V., Norton, W. H., Miura, K., and Gilmour, D. (2008) Internal FGF-signaling coordinates cell momement with the migrating lateral line primordium. In preparation

Own project-related publications (submitted / in preparation)

Haas, P., Lecaudey, V., Colombelli, J., Stelzer, E. H., and Gilmour, D. (2008) Mechanical Regluation of Directional Migration and Organ Assembly in the Zebrafish lateral line. In preparation.

Lecaudey, V., Cakan, G., Norton, W. H., Miura, K., and Gilmour, D. (2008) Internal FGF-signaling coordinates cell momement with the migrating lateral line primordium. In preparation

Selected publications from other projects outside the SFB since 2005

Lecaudey, V., and Gilmour, D. (2006) Organizing moving groups during morphogenesis. Curr Opin Cell Biol 18: 102-107

Pouthas, F., Girard, P., Lecaudey, V., Gilmour, D., Boulin, C., Pepperkok, R., and Reynaud, E. G. (2008) The Golgi apparatus and centrosome positions depend on geometrical constraints of the substratum during cell migration. Journal of Cell Science in press

Darren Gilmour

EMBL Heidelberg

Meyerhofstr.1

69117 Heidelberg

Phone:  06221-3878294
Fax:      06221-3878578
email:    Gilmour(at)embl.de