Other groups are also finding evidence that Wnt signaling is important for differentiation and lineage switching. Elaine Fuchs and colleagues at Rockefeller University in New York, for example, have disrupted Wnt signaling to produce sebaceous gland formation inside mouse hair follicles [5
], while Fiona Watt and colleagues from Cancer Research UK found that the level of β-catenin determines whether keratinocytes in the skin differentiate into hair follicles [6
]. And Lothar Henighauser and colleagues at the National Institutes of Health used over-expression of β-catenin to create areas of keratinized skin in mouse prostate glands [7
]. Together, these studies could provide an important bridge between developmental biology and stem cell research, according to Lee Niswander, of the Memorial Sloan Kettering Cancer Center in New York.
"It would be really fun to see how these results can inform stem cell biology, and capitalize on these ideas. We all laugh in the developmental field that there are about five key signaling molecules that can regulate so many things in embryonic development - Wnt, FGF [fibroblast growth factor], TGF-β [transforming growth factor-β], Hedgehog and Notch. In all different stem cell lines you need these signaling components at some level and at some time to drive differentiation, but what we really don't understand is how to drive specific differentiation."
Hogan hopes the new data may provide clues for how to use stem cells from adults for therapeutic purposes. "If you could take a biopsy of an adult tissue like the intestine, where we know there are stem cells, grow them in culture, and expose the dividing stem cells to a cocktail of signaling factors, it might be possible to switch them into progenitors of other endodermal tissue types, but this is a long shot," she says.
But, according to Cardoso, perhaps the most interesting aspect of looking at Wnt signaling may be in shedding light on some of the earliest observations about metaplasia. In the 1950s, embryologists treated the skin of chick embryos with retinoids (vitamin A derivatives) and could produce patches of respiratory epithelium with secretory cells and beating cilia [8
]. Conversely, researchers have also described rats in which vitamin A deficiency produces the opposite effect: parts of the trachea are transformed from respiratory epithelium into squamous epithelium [9
]. "Many of the big observations have already been made, but people at that time had no idea of how to proceed or get into a mechanism. Who knows if at least some of these are related to Wnt signaling or not, but we have to look at this more carefully," says Cardoso. And with the advent of genome manipulation and large-scale screening for gene activity, finding the molecules that underlie these crucial developmental and pathological events is beginning to become a reality.