Notch signalling is important for forming new brain cells, new blood cells and even the body plan of new organisms. Even though the signaling is ubiquitous and highly regulated, researchers had not previously identified a soluble protein ligand that blocks Notch receptors. Reporting in Nature Cell Biology, researchers at the Johann Wolfgang Goethe University School of Medicine in Frankfurt have now done so1.

“The take-home message is that a secreted Notch modulator exists in the brain that drives the formation of neurons from adult neural stem cells,” explains author Mirko Schmidt. “It was most surprising to detect EGFL7 in this organ as it has been described to be specific for the remodelling vasculature.” The protein, called epidermal growth factor-like domain 7 (EGFL7), binds the extracellular domains of all Notch receptors (Notch 1–4) and, in fact, seems to compete with known Notch ligands Jagged1 and Jagged2.

The researchers assessed the self-renewal of neural stem cells by letting them grow into structures called neurospheres and then disaggregating them and seeing how many new neurospheres formed. When both mouse and human EGFL7 was added to cultures of mouse neural stem cells growing into neurospheres, self-renewal rates decreased by 67%. When EGFL7 production was blocked with antisense constructs, self-renewal rates increased by 79%.

What's more, other evidence indicated that Notch signalling can also regulate EGFL7 in a negative feedback loop: inhibiting Notch signalling boosted rates of EGFL7 expression fivefold, for example. Studies of EGFL7 expression in the mouse brain found that the cortex had high levels of the protein (primarily from mature neurons). Levels in the subventricular zone, where neurogenesis occurs, were low.

Finally, the researchers studied how EGFL7 affects neural stem cell differentiation. Notch signalling appears to encourage differentiation into astrocytes. Not surprisingly, neural stem cells treated with EGFL7 were more likely to become neurons or oligodendrocytes. A soluble protein that can antagonize Notch signalling promises a variety of practical applications in culturing and differentiating cells. More importantly, it indicates a previously unrecognized mechanism to guide how Notch signalling controls adult neural stem cells.