Image courtesy of Hannele Ruohola-Baker, University of Washington, Seattle

One of the properties that make stem cells special is their ability to ignore signals that tell surrounding cells to stop dividing. Previously, how they do this has been something of a mystery, but two new studies now reveal that small RNAs hold the key.

Zamore and colleagues uncovered this role for small RNAs after identifying a new component of the miRNA processing machinery in Drosophila melanogaster. They showed that the dsRNA-binding protein Loquacious (LOQS) is essential for the processing of miRNA precursors by the Dicer 1 (DCR1) endonuclease and for the function of small interfering RNAs that silence repetitive regions. Intriguingly, loqs mutant female flies are sterile and have small ovaries.

Mutations that block the division or maintenance of germline stem cells (GSCs) are known to give rise to similar phenotypes, as they block the formation of egg chambers (which produce oocytes) by GSCs. The authors found that although GSCs were absent from loqs mutant females at 3–4 days of age, some oocytes were produced, so GSCs must have been present initially. Zamore and colleagues concluded that lack of LOQS function, and therefore small RNA production, leads to loss of GSCs due to either death or a failure to divide and produce daughter cells.

In the second study, Ruohola-Baker and colleagues showed that small RNAs have a role specifically in GSC division. They generated flies with ovaries containing GSC clones that were mutant for dcr1, and therefore completely lacked miRNAs. The number of GSCs was not altered, indicating that GSC maintenance is not impaired. However, the ovaries contained fewer developing egg chambers, which again indicated a defect in the ability of GSCs to give rise to these structures. In particular, the numbers of GSCs in S, G2 and M phase were reduced, indicating that these cells are blocked in G1 phase.

This study also showed that miRNAs normally allow GSCs to escape cell-cycle arrest by blocking the expression of Dacapo (DAP), a cell-cycle inhibitor. A dcr1 mutation increased the number of DAP-positive GSCs, and Dap overexpression produced a dcr1-like phenotype. Furthermore, reducing DAP levels rescued the defects in dcr1 mutants.

These studies show an essential role of small RNAs in Drosophila GSCs, enabling these cells to escape the controls on division that other cells obey. An important aim now will be to determine whether this function of small RNAs is conserved in mammalian stem cells.