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Guidance of Primordial Germ Cell Migration by the Chemokine SDF-1

November 27, 2002

Identification of the molecular cues governing cell migration is of major importance for the understanding of tissue and organ development and for therapy in cases of diseases resulting from aberrant cell movement.

Primordial Germ Cell (PGC) migration is a useful model for studying directional cell movement. During embryonic development, PGCs have to travel long distances from their initial site of formation to their final destination - the gonad, where they give rise to either sperm or eggs. The identity of the molecules responsible for guiding the PGCs towards their target has been unknown.

We have chosen to study PGC migration in zebrafish, benefiting from the fast embryonic development, the optical clarity, and the availability of mutant strains and genomic tools. In this work we showed that zebrafish PGCs are guided by the chemokine stromal-cell derived factor -1 (SDF-1) during early stages of embryonic development. SDF-1 and its receptor CXCR4 are known to play an important role in mobilizing blood stem cells, leukocytes and neuronal cells and were shown to be involved in pathological conditions such as cancer metastasis, HIV infection and arthritis.

We demonstrated that CXCR4 is expressed in the PGCs of zebrafish throughout their migration, enabling them to sense and move towards regions in the embryo expressing high levels of SDF-1. The dynamic expression pattern of SDF-1 along the migration route of PGCs guides them with precision towards their final target - the future gonad.

Interfering with SDF-1 signalling results in severe migration defects. For example, when the activity of SDF-1 or its receptor, CXCR4, is reduced, the PGCs maintain their motile behaviour but are unable to detect directional cues and they end up dispersed throughout the embryo. The ability of SDF-1 to direct PGC migration was demonstrated by its ability to attract PGCs towards positions where they are normally not found. In experiments where the endogenous SDF-1 activity was inhibited, introduction of SDF-1 at random sites within the embryo redirected PGC migration towards these abnormal positions.

Together, we have identified the signals that coordinate PGC migration in zebrafish and currently, we are trying to extend these findings to other organisms. In addition, the regulation of PGC migration in zebrafish through the attraction by SDF-1 is relevant for the regulation of cell movement in human diseases; for example when T-cells accumulate in synovium of rheumatoid arthritis patients, or when breast cancer cells metastasize to tissues expressing SDF-1 like the bone marrow, liver and lung. Zebrafish PGC migration could thus serve as a model to study those diseases. In this context, PGC migration could be used as an in vivo assay to screen for molecular compounds that interfere with CXCR4/SDF-1 signalling pathway.

Institut National de Recherche en Informatique et en Automatique - Le Chesnay (INRIA)