NCSCs cultured with BMP and Wnt maintain stem cell markers (green and red).

Stem cell fate is determined by growth factors. But on page 309, Kléber et al. show that the right combination of growth factors can also keep cells from committing to a differentiated fate. Neural crest stem cells (NCSCs), they find, are maintained by the dual punch of Wnt and BMP.NCSCs have the potential to become many different cell types. For example, Wnt exposure of NCSCs results in sensory neurons, BMP exposure results in autonomic neurons, TGFβ exposure results in smooth muscle, and NRG1 exposure results in glia. Most NCSCs see Wnt as they leave the neural tube and start to migrate throughout the developing embryo. Yet not all become sensory neurons. The new results indicate that some escape because BMP is present to block Wnt's differentiation activity, as has also been seen in bone precursors.

More than a simple blockade to a sensory fate, the combination of Wnt and BMP actually instructs NCSCs to maintain their stem cell qualities. In their presence, all differentiated fates were avoided, and stem cell markers were expressed for days in culture. Upon Wnt withdrawal, NCSCs were then still able to differentiate in response to NRG1, TGFβ, or BMP.

Responsiveness to Wnt, however, was diminished after several days in culture. A few days after emerging from the neural tube, NCSCs in vivo were also less responsive to Wnt. This property might restrict the place and time of sensory neuron formation. Since Wnt is no longer potent, other factors may have to assume control of stem cell maintenance. Or perhaps an early blast of Wnt and BMP sustains stem cells until they find a differentiation signal.

A complex of downstream effectors of BMP and Wnt signaling—Sox and β-catenin, respectively—has been found in bone and endodermal cells. Whether this combination turns on genes for stem cell maintenance in NCSCs remains to be seen.