From the moment a fertilized egg starts dividing, its cellular progeny fall into a highly coordinated regimen of motion, growth, and change. As one cell quickly becomes hundreds, some cells passively ride the waves of dividing cells, while others must navigate uncharted territory to reach their destination. Such is the fate of germ cells, the guardians of genetic inheritance. In the fruitfly Drosophila, primordial germ cells are among the first cells to develop, appearing in the posterior embryo. Yet the cells that form the somatic tissue of the gonad—where germ cells mature into sperm and eggs—arise in the middle layer of cells, called the mesoderm. Primordial germ cells must make their way through the densely packed cells that form the posterior midgut epithelium and then negotiate a series of topographical landmarks before arriving at the gonadal mesoderm cells.

The genes and molecules guiding germ cells' improbable migration through the posterior midgut are not well known. Scientists have only recently discovered that a chemokine receptor called CXCR4—a member of the G protein-coupled receptors (GPCRs), the largest family of cell-surface receptors—controls the migratory pattern of a variety of cell types, including leukocytes, neurons, and cancer cells. Subsequent studies in zebrafish and mice showed that this receptor and its ligand (bound molecule) guide germ cell migration in vertebrates. Now Ruth Lehmann and colleagues have identified a novel type of GPCR gene called tre1 that is required for the earliest stage of active germ cell migration—passage through the posterior midgut epithelium.

Until now, no mutations had been identified that affected transepithelial migration without disrupting the midgut itself. To identify likely candidates, Lehmann et al. introduced a series of mutations in Drosophila, ranging from overexpression to no expression, and stained the germ cells to observe the mutations' effects on germ cell migration. A laborious series of experiments led the authors to a gene that had a very interesting germ-cell phenotype (the physical effect of the mutation) when misexpressed in these cells. After closer analysis, they discovered that the gene was not normally expressed in germ cells and that loss of gene function had no effect on these cells. But the authors realized they were on the right track since the protein sequence of the gene was a GPCR and another closely related gene produced a striking germ-cell phenotype: in some cases, a gonad wound up with only one out of the typical 12–15 germ cells, while the other cells remained trapped in the gut.

This gene, called tre1, had previously been considered a taste receptor gene until the true taste receptor was discovered. Expression pattern studies of tre1 showed that it is expressed in germ cells and that germ cells lacking the Tre1 GPCR display a significant defect in migration. Maternal genes (gene products from the mother that wind up in the embryo) regulate the earliest stages of development, and the researchers conclude that normal germ-cell migration through the posterior midgut—the first active migratory step—depends on maternal tre1 RNA and protein deposited in the germ cells. And tre1 may be needed only for this early step, since the few tre1-mutant cells that do pass through the epithelium still make it to the gonads. Given the fact that tre-1 already had a name, Lehmann et al. decided to keep its abbreviation but, following genetics tradition, change its meaning to describe the phenotype of its mutation: trapped in endoderm. While it is unclear what ligand activates the Tre1 receptor, the scientists identified a likely downstream target of the receptor, called Rho1. When this well-known GPCR signaling component is disrupted, germ cells cannot pass through the posterior midgut epithelium.

Tre1, which belongs to a new subclass of GPCRs, has three Drosophila homologs that are expressed in various types of migrating cells. Because GPCRs are evolutionarily ancient proteins, Tre1 and its homologs may have conserved functions in directional cell migration. Lehmann et al. propose that Tre1 functions similarly to related chemokine receptors active during transepithelial migration during an immune response—a process that is not well understood—and that this new group of GPCRs could well control this process, as well as a variety of other migratory functions. If it turns out that these same molecules are also active in cancer—in which invasive migratory behavior leads to tumor cell metastasis—scientists will have a promising lead on finding ways to block their action in targeted therapies. Lehmann et al. hope these results will lay the foundation for such efforts by shedding light on the molecular mechanisms that drive cell migration through tissue.

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Drosophila germ cells migrating through the gut epithelium

https://doi.org/10.1371/journal.pbio.0000088.g001