When, after screening over 10,000 mutant Drosophila ovaries, Jean-René Huynh and his colleagues at the University of Paris singled out a mutation that caused the egg chambers to be smaller than usual, they were a bit puzzled. The germline stem cells were disappearing from the niche, and it wasn't because the cells were dying: blocking apoptosis did not boost their numbers. Instead, stem cells must disappear because they differentiate. "This told us that the mutant was involved in self-renewal, so it became very interesting," said Huynh.

The mutation was traced back to a single amino acid substitution in a highly conserved gene named wicked (wcd). Previous research had shown that its human homolog is localized in the nucleolus, a part of the nucleus where ribosomes are made. The yeast homolog is part of a complex that plays an important role in ribosome biogenesis. "Using immunochemistry we showed that, in vivo, wcd is also part of a nucleolar complex," said Huynh. This complex, called U3snoRNP, is involved in the maturation of ribosomal RNA (rRNA). Knocking down wcd by RNAi prevented these rRNAs from being cleaved properly, which caused a build up of immature rRNA in the nucleolus. This proved that wcd is essential for ribosome synthesis.

Understanding why irregular ribosome synthesis caused small egg chambers required another instance of serendipity. "We decided to use wcd as a nucleolar marker in another live imaging project we were starting in the lab," continued Huynh. "That's when we noticed that there was asymmetry." Although wcd is present in all cells, the team noticed that a tiny fraction of the protein formed particles during metaphase. When a germline stem cell (GSC) divided, these particles always remained within the GSC lineage rather than being passed into the differentiating daughter. "This could explain the phenotype," said Huynh. GSCs grow and divide more quickly than differentiating cells, he says. "Maybe GSCs need more wcd to function than differentiating cells."

Because wcd is present in all cells, but only the particles segregate, it's unclear whether the distribution is really asymmetric, notes Yukiko Yamashita of the University of Michigan in Ann Arbor. Additionally, it's unclear how, or even if, the segregated particles maintain GSC identity. One possibility is that only the wcd contained in the particles is active and helps stem cells produce ribosomes faster than differentiating cells. "We are not sure that wcd itself is the important thing — the particles contain other upstream regulators of ribosome biogenesis which may be more important than wcd itself," Huynh explains. Perhaps one of the most interesting things about wcd, he says, is that it is not affected by dpp, one of the key regulators of stem cell fate in the Drosophila ovary. Increasing dpp signalling did not affect the ability of wcd to segregate asymmetrically, although it did cause both daughter cells to behave like stem cells. This suggested to the team that the asymmetry is intrinsic but is not sufficient to induce differentiation.

The work fits well with a model in which specific proteins (Brat and Mei-P26) inhibit ribosome biogenesis in smaller, differentiating daughter cells, whereas wcd encourages biogenesis in larger GSCs. "This is very intriguing," says Yamashita, "but there is a gap between the asymmetry of the particle structures and their function." One way of understanding more about the active component would be to identify another protein that co-localizes with wcd and is only present in the particles, or even ablating the particles completely with lasers to see what happens. "The work in the field at the moment certainly points to a model in which increased ribosome biogenesis gives stem cells a competitive advantage." Huynh says. The next steps are to figure out why that is so.