Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Two distinct modes of guidance signalling during collective migration of border cells


Although directed migration is a feature of both individual cells and cell groups, guided migration has been studied most extensively for single cells in simple environments1,2. Collective guidance of cell groups remains poorly understood, despite its relevance for development and metastasis3. Neural crest cells and neuronal precursors migrate as loosely organized streams of individual cells4,5, whereas cells of the fish lateral line6,7, Drosophila tracheal tubes and border-cell clusters8 migrate as more coherent groups. Here we use Drosophila border cells to examine how collective guidance is performed. We report that border cells migrate in two phases using distinct mechanisms. Genetic analysis combined with live imaging shows that polarized cell behaviour is critical for the initial phase of migration, whereas dynamic collective behaviour dominates later. PDGF- and VEGF-related receptor and epidermal growth factor receptor act in both phases, but use different effector pathways in each. The myoblast city (Mbc, also known as DOCK180) and engulfment and cell motility (ELMO, also known as Ced-12) pathway is required for the early phase, in which guidance depends on subcellular localization of signalling within a leading cell. During the later phase, mitogen-activated protein kinase and phospholipase Cγ are used redundantly, and we find that the cluster makes use of the difference in signal levels between cells to guide migration. Thus, information processing at the multicellular level is used to guide collective behaviour of a cell group.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: ELMO is essential in early but not in late border-cell migration.
Figure 2: Shc is downstream of EGFR, and PLCγ and Raf/MAPK are required for late RTK signalling.
Figure 3: Live imaging of border-cell migration.
Figure 4: Guidance of border-cell clusters by collective decision comparing signal levels between cells.


  1. Parent, C. A. & Devreotes, P. N. A cell’s sense of direction. Science 284, 765–770 (1999)

    ADS  CAS  Article  Google Scholar 

  2. Servant, G. et al. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287, 1037–1040 (2000)

    ADS  CAS  Article  Google Scholar 

  3. Friedl, P., Hegerfeldt, Y. & Tusch, M. Collective cell migration in morphogenesis and cancer. Int. J. Dev. Biol. 48, 441–449 (2004)

    CAS  Article  Google Scholar 

  4. Kulesa, P. M. & Fraser, S. E. Neural crest cell dynamics revealed by time-lapse video microscopy of whole embryo chick explant cultures. Dev. Biol. 204, 327–344 (1998)

    CAS  Article  Google Scholar 

  5. Lois, C., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Chain migration of neuronal precursors. Science 271, 978–981 (1996)

    ADS  CAS  Article  Google Scholar 

  6. Ghysen, A. & Dambly-Chaudiere, C. Development of the zebrafish lateral line. Curr. Opin. Neurobiol. 14, 67–73 (2004)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  8. Starz-Gaiano, M. & Montell, D. J. Genes that drive invasion and migration in Drosophila. Curr. Opin. Genet. Dev. 14, 86–91 (2004)

    CAS  Article  Google Scholar 

  9. Rørth, P. Initiating and guiding migration: lessons from border cells. Trends Cell Biol. 12, 325–331 (2002)

    Article  Google Scholar 

  10. Duchek, P., Somogyi, K., Jékely, G., Beccari, S. & Rørth, P. Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107, 17–26 (2001)

    CAS  Article  Google Scholar 

  11. Duchek, P. & Rørth, P. Guidance of cell migration by EGF receptor signaling during Drosophila oogenesis. Science 291, 131–133 (2001)

    ADS  CAS  Article  Google Scholar 

  12. Jekely, G., Sung, H. H., Luque, C. M. & Rorth, P. Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. Dev. Cell 9, 197–207 (2005)

    CAS  Article  Google Scholar 

  13. Brugnera, E. et al. Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex. Nature Cell Biol. 4, 574–582 (2002)

    CAS  Article  Google Scholar 

  14. Rørth, P., Szabo, K. & Texido, G. The level of C/EBP protein is critical for cell migration during Drosophila oogenesis and is tightly controlled by regulated degradation. Mol. Cell 6, 23–30 (2000)

    Article  Google Scholar 

  15. Bose, R. et al. Phosphoproteomic analysis of Her2/neu signaling and inhibition. Proc. Natl Acad. Sci. USA 103, 9773–9778 (2006)

    ADS  CAS  Article  Google Scholar 

  16. Luschnig, S., Krauss, J., Bohmann, K., Desjeux, I. & Nüsslein-Volhard, C. The Drosophila SHC adaptor protein is required for signaling by a subset or receptor tyrosine kinases. Mol. Cell 5, 231–241 (2000)

    CAS  Article  Google Scholar 

  17. Fulga, T. A. & Rørth, P. Invasive cell migration is initiated by guided growth of long cellular extensions. Nature Cell Biol. 4, 715–719 (2002)

    CAS  Article  Google Scholar 

  18. Reichman-Fried, M., Minina, S. & Raz, E. Autonomous modes of behavior in primordial germ cell migration. Dev. Cell 6, 589–596 (2004)

    CAS  Article  Google Scholar 

  19. Lloyd, T. E. et al. Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila. Cell 108, 261–269 (2002)

    CAS  Article  Google Scholar 

  20. Pai, L. M., Barcelo, G. & Schupbach, T. D-cbl, a negative regulator of the Egfr pathway, is required for dorsoventral patterning in Drosophila oogenesis. Cell 103, 51–61 (2000)

    CAS  Article  Google Scholar 

  21. Yoo, A. S., Bais, C. & Greenwald, I. Crosstalk between the EGFR and LIN-12/Notch pathways in C. elegans vulval development. Science 303, 663–666 (2004)

    ADS  CAS  Article  Google Scholar 

  22. Ghabrial, A. S. & Krasnow, M. A. Social interactions among epithelial cells during tracheal branching morphogenesis. Nature 441, 746–749 (2006)

    ADS  CAS  Article  Google Scholar 

  23. Gong, W. J. & Golic, K. G. Ends-out, or replacement, gene targeting in Drosophila. Proc. Natl Acad. Sci. USA 100, 2556–2561 (2003)

    ADS  CAS  Article  Google Scholar 

  24. Ghiglione, C. et al. The transmembrane molecule Kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. Cell 96, 847–856 (1999)

    CAS  Article  Google Scholar 

  25. Borghese, L. et al. Systematic analysis of the transcriptional switch inducing migration of border cells. Dev. Cell 10, 497–508 (2006)

    CAS  Article  Google Scholar 

  26. Zhou, Z., Caron, E., Hartwieg, E., Hall, A. & Horvitz, H. R. The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev. Cell 1, 477–489 (2001)

    CAS  Article  Google Scholar 

  27. Rabut, G. & Ellenberg, J. Automatic real-time three-dimensional cell tracking by fluorescence microscopy. J. Microsc. 216, 131–137 (2004)

    MathSciNet  CAS  Article  Google Scholar 

Download references


We thank EMBL-ALMF, K. Somogyi and A. M. Voie for help, Y. Cohen and E. Schejter for sharing, and K. Brown, V. Hietakangas, D. Gilmour and S. Cohen for comments. This work was supported by Marie Curie FP6 Intra-European fellowships (A.C. and M.P.), the Academy of Finland and the Helsingin Sanomat Centennial Foundation (M.P.), HFSP (J.M.), EMBO (C.M.L.) and EMBL.

Author Contributions M.P. and A.C. contributed equally to this work and performed all culturing and live imaging experiments. J.M. contributed to the elmo knockout. C.M.L. and T.A.F. performed the protein interaction and genetic analysis of EGFR, respectively. A.B. performed all remaining analyses. P.R. wrote the manuscript.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Pernille Rørth.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S5 with Legends, Supplementary Table S1, Supplementary Videos Legends, Supplementary Methods and additional references (PDF 5340 kb)

Supplementary Video 1

This file contains Supplementary Video 1 showing early migration. Early cluster shows elongated morphology with a single cell leading the cluster. Migration is rapid and highly directional (compare to S3). (MOV 5109 kb)

Supplementary Video 2

This file contains Supplementary Video 2 showing early cluster migration followed by shuffling of the cluster. (MOV 5096 kb)

Supplementary Video 3

This file contains Supplementary Video 3 showing later stage of migration (after shuffling phase). Cluster is much rounded thatduring early phase, with less obvious leading cell and more obvious migration by other cells in the cluster. Migration speed is slower that early phase (~0.4µm/min). (MOV 5098 kb)

Supplementary Video 4

This file contains Supplementary Video 4 showing example of cluster shuffling. Cells move and exchange positions often, with little net movement of the cluster. Note that shuffling behaviour generally occurs at junction of posterior most nurse cells. (MOV 5120 kb)

Supplementary Video 5

This file contains Supplementary Video 5 showing dominant negative guidance receptors. Overexpression of DN-PVR and DN-EGFR blocks polarized migration. Cells extend processes but with little net effect. Some backward movement is seen. Genotype: yw,hs-FLP,UAS-CD8-GFP/+; UAS-DN-Egfr, If, slbo1310, / slbo-Gal4, UAS-DN-Pvr (MOV 5111 kb)

Supplementary Video 6

This file contains Supplementary Video 6 showing over-expression of PVF-1 ligand in border cells causes the cluster to adopt a rounded morphology, similar to late phase migration. Cells shuffle, rapidly extend and retract processes and the cluster migrates slowly in the correct direction. Genotype: EPg11235(Pvf1)/+; UAS-CD8-GFP/+; slbo-Gal4/+ (MOV 4117 kb)

Supplementary Video 7

This file contains Supplementary Video 7 showing mid-late migration in control egg chamber.All cells are labeled with nuclear GFP and the relative movement of individual border cell nuclei within the cluster can be appreciated. Genotype: w, hsFLP,sn/+; nos-Gal4-VP16/ ubi-NLS-GFP, FRT40 (MOV 5261 kb)

Supplementary Video 8

This file contains Supplementary Video 8 showing PVF-1 over-expression in germ line. All cells are labeled with nuclear GFP. Overall movement is less severely affected than when PVF1 in expressed in border cells, but despite the early stage the movement is shuffling and slow. Genotype: w,hsFLP,sn/ EPg11235(Pvf1); nos-Gal4- VP16/ ubi-NLS-GFP, FRT40 (MOV 6043 kb)

Supplementary Video 9

This file contains Supplementary Video 9 showing mosaic cluster with PVR overexpression in a single border cell. The c522 driver is used to give mild overexpression of PVR in one outer border cell (as in Figure 4), and also drives GFP expression, which is quite faint. Genotype: y,w,hsFLP,UAS-CD8GFP/ y, w,hsFLP,UAS-CD8GFP; tubGal80,FRT40/ FRT40,42; c522-Gal4/UAS-PVR (MOV 5103 kb)

Supplementary Video 10

This file contains Supplementary Video 10 showing mosaic cluster with 2 hrs mutant cells.Mutant cells marked by GFP expression; one of the hrs mutant cells is bright from the beginning and in the front. Later, a second, faintly positive (mutant) cell is also seen. One hour movie. Genotype: y,w,hsFLP,UAS-CD8GFP/+; tubGal80,FRT40/ HrsD28,FRT40; slbo-Gal4/+. (MOV 3683 kb)

Supplementary Video 11

This file contains Supplementary Video 11 showing mosaic cluster with 2 elmo mutant cells.Mutant cells marked by GFP expression. Second phase of migration, including tumbling in which front position alternates between elmo mutant and control (GFP negative) cells. Genotype: y,w,hsFLP,UASCD8GFP/+;tubGal80,FRT40/ elmoKO,FRT40;slbo-Gal4/+. In early phases (other movies), elmo mutant cells usually stayed in the rear. (MOV 3153 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bianco, A., Poukkula, M., Cliffe, A. et al. Two distinct modes of guidance signalling during collective migration of border cells. Nature 448, 362–365 (2007).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing