Journal Article

Dynamic filopodia are required for chemokine-dependent intracellular polarization during guided cell migration in vivo

Messerschmidt, Esther-Maria, Reichman-Fried, Michal, Banisch, Torsten U, Maugis, Benoît, Meyen, Dana, Tarbashevich, Katsiaryna, Grimaldi, Cecilia, Wittwer, Carolina, Raz, Erez

2015

Overview

Cell migration and polarization is controlled by signals in the environment. Migrating cells typically form filopodia that extend from the cell surface, but the precise function of these structures in cell polarization and guided migration is poorly understood. Using the in vivo model of zebrafish primordial germ cells for studying chemokine-directed single cell migration, we show that filopodia distribution and their dynamics are dictated by the gradient of the chemokine Cxcl12a. By specifically interfering with filopodia formation, we demonstrate for the first time that these protrusions play an important role in cell polarization by Cxcl12a, as manifested by elevation of intracellular pH and Rac1 activity at the cell front. The establishment of this polarity is at the basis of effective cell migration towards the target. Together, we show that filopodia allow the interpretation of the chemotactic gradient in vivo by directing single-cell polarization in response to the guidance cue. Some of the cells in an animal embryo have to migrate long distances to reach their final positions; that is to say, to reach the locations where they will participate in the formation of tissues and organs. The migration of cells is also important throughout the entire lifespan of an animal. White blood cells, for example, must be able to move within tissues to search for and fight infections as well as to detect and remove abnormal cells. The front end of a migrating cell typically protrudes. The back of the cell is then pulled and detaches, which allows the whole cell to move forward. Migrating cells generate thin finger-like projections known as filopodia that have been suggested to help the cell sense their external environments and follow chemical cues. It is not clear what happens to a migrating cell in a living organism if the formation of its filopodia is impaired, or even how filipodia help the normal migration of cells in animals. To define how filopodia help to guide migrating cells in an animal, Meyen et al. analyzed the migration of cells called ‘primordial germ cells’ (or PGCs) in zebrafish. These cells form very early on in development of a zebrafish embryo at a position that is far away from their final location (in the testes or ovaries where they will go on to form sperm or egg cells respectively). Meyen et al. revealed that cells that are exposed to the guidance cue (a protein called a chemokine) form more filopodia at their front compared to their rear. The filopodia formed at the cell front also extend and retract more frequently. Meyen et al. further observed that the specific chemokine that guides the cells can bind to the filopodia and enter the cell. This leads to a signal inside the cell that tells the cell to move in the direction where more of the chemokine is found. Indeed, altering the distribution and number of filopodia around the cell's edge decreases the ability of the primordial germ cells to reach their targets. Together, this work shows that the filopodia at the front end of cells are required for sensing the chemokines that guide cell movement. Further work is required to understand the mechanism that determines the distribution of filopodia on the surface of migrating cells, and the role of chemokines in the process. Moreover, this work may also be relevant for understanding the migration of cancer cells, because several types of cancer can invade new tissues by following directional cues including chemokines.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Cell adhesion & migration / cell migration / Cell Movement / Cell Polarity / Cell surface / chemokine / Chemokine CXCL12 - metabolism / Chemokines / chemotaxis / Danio rerio / Developmental Biology and Stem Cells / Embryo, Nonmammalian - metabolism / Embryos / Endocytosis - drug effects / Experiments / Filopodia / germ cell / Germ cells / Germ Cells - cytology / Germ Cells - metabolism / Inflammation / Intracellular / Intracellular Space - metabolism / Lasers / Leukocyte migration / Metastasis / Models, Biological / pH effects / Polarity / Polarization / Proteins / Pseudopodia - metabolism / Rac1 protein / Receptors, CXCR4 - metabolism / Zebrafish - embryology / Zebrafish - metabolism / Zebrafish Proteins - metabolism