Reporting in Science, Wang and Lin tackle one of the most fundamental problems in stem-cell biology: how does a stem cell decide that, when dividing, it should make at least one more of itself — rather than generating two more-specialized cell types? The authors find that a key to such 'self-renewal' is, at least for one type of stem cell, a translational repressor known as Nanos.

Recent years have seen much progress in understanding the extrinsic signals that regulate stem-cell self-renewal. But the intrinsic cues have, for most stem cells, been more of a mystery. Wang and Lin approached the problem by looking at fruitfly ovaries, and specifically germline stem cells (GSCs), which have certain benefits as a model system — including their distinctive morphology. GSCs are formed from primordial germ cells at the larval/pupal transition. In adult females, GSCs can both self-renew and generate differentiating cell types, namely cystoblasts, which go on to produce egg chambers.

It was already known that Nanos contributes to the production of eggs, but exactly what it does was less clear. To start to find out, Wang and Lin constructed a nanos transgene that is switched on by heat shock. They used this transgene to restore functional Nanos to female embryos with nanos mutations. Then, after the adults emerged from the pupa, they switched the transgene off. The result was that the number of GSCs dropped sharply in comparison with wild-type flies — as did the number of egg chambers (presumably because there were fewer GSCs to generate them). So, Nanos is required continuously for GSCs to self-renew.

In this experiment, Nanos was switched on and off in the whole fly. It cannot be seen from this, however, whether the Nanos signal is intrinsic or extrinsic to GSCs. To find out, the authors removed the protein only from GSCs. They concluded that Nanos is an intrinsic regulator of GSC self-renewal — and that it works by preventing these cells from differentiating. Moreover, it probably functions by forming complexes with the RNA-binding protein Pumilio.

Nanos–Pumilio complexes are known to bind to Nanos-response elements in target mRNAs, repressing their translation. So one future avenue of research will be to identify the mRNAs that are repressed by Nanos–Pumilio in GSCs. It will also be interesting to see how the activities of this intrinsic regulator are integrated with extrinsic signals — and whether it behaves similarly in other stem cells, and other species.