As a young researcher, Elaine Fuchs was drawn to skin because of all that this most accessible of organs could reveal about cellular development. It is, she says, “a wonderful experimental system” — one that led her and her colleagues to discover a molecule responsible for fine-tuning the switch that causes a stem cell to produce a specialized cell.

Our skin's surface, or epidermis, comprises several layers of cells, all of which begin life as stem cells in the innermost 'basal' layer. From there, they stop dividing and move towards the outer layer, developing into specialized protective cells through a process known as differentiation as they go. For years, Fuchs, now a Howard Hughes Medical Institute cell biologist based at the Rockefeller University in New York, and others used cultured cells and animal studies to tease out the details of how cells migrate through the epidermis. By 2004, much had been learned about the mechanisms that demarcate the switch from proliferation to differentiation.

Then microRNAs appeared on the scene. These short, single-stranded RNA molecules turn down the production of certain proteins by binding to the mRNAs that normally serve as 'recipes' for those proteins' synthesis. “We started to wonder whether microRNAs might also be involved in the switch,” says Fuchs.

Working with mice, Fuchs' postdoc Rui Yi found a wealth of microRNAs in skin at various stages of the animals' development. One in particular, named miR-203, stood out. Early in embryonic development, when the epidermis comprises just one layer, Yi found no miR-203 expression. But by the time these stem cells began to generate differentiating epidermal layers, miR-203 levels were high. This suggests that the microRNA might be involved in the switch to stratification and differentiation.

So Fuchs and her collaborators began investigating miR-203's function — work that involved many late nights in the lab. “I received plenty of emails from Rui at 2 and 3 a.m.,” Fuchs acknowledges. But the results were worth the hard work. The team discovered that miR-203 interacts with the mRNA for a protein that is known to help epithelial stem cells maintain their proliferative abilities or 'stemness' (see page 225). The prevalence of this protein, called p63, was reduced whenever miR-203 was expressed.

Knockout of p63 in mice leads to stem-cell depletion and severe developmental abnormalities. Fuchs and her team found that precocious expression of miR-203 in mouse basal-layer cells causes lethal flaws that resemble those of p63-knockout mice. Conversely, miR-203 knockdown resulted in p63 levels being boosted, and sustained cell proliferation in epidermal layers beyond the basal layer.

Fuchs suggests that, in skin, miR-203 may function as a fine-tuning system for the switch from stem-cell proliferation to differentiation. “When a cell commits to differentiate, the first step is to induce changes in gene expression and generate different mRNAs,” she says. “But simultaneously reducing protein expression makes for a cleaner, swifter change in the transition.”

MicroRNAs may have roles in many developmental processes and some cancers. MiR-203 might be a therapeutic target for a type of cancer known as squamous cell carcinoma, Fuchs suggests. She adds that “if microRNAs turn out to be broadly important in controlling the balance between stem cells and differentiation, their therapeutic potential could be even greater”.