Top-Notch result

Notch signalling is probably best known for its pivotal role in neural cell fate choice through lateral inhibition. In the Drosophila neuroectoderm, for example, cells that are destined for a neural fate upregulate the Notch ligand Delta, which activates Notch signalling in neighbouring cells, causing them to adopt an epidermal fate through the repression of the achaete / scute proneural genes. However, as Ramain et al. have now shown, lateral inhibition is not the only pathway that Notch can use to prevent neural differentiation.

The small sensory bristles (microchaetae) on the fly thorax are known to be specified through lateral inhibition, and the authors screened for mutations that resulted in their loss. They identified several Notch mutant alleles that produced such a phenotype, and they named these alleles N^Mcd (Mcd stands for microchaetae defective). These were classed as gain-of-function mutations, because they seemed to enhance Notch's normal function in repressing neural cell fate. The authors reasoned that if the mutant forms of Notch acted through the lateral inhibition pathway, then inactivating downstream components of this pathway (such as Suppressor of Hairless (Su(H)) and Groucho) in the N^Mcd mutants should restore the development of microchaetae. However, no such effect was seen, indicating that another pathway must be involved.

The adaptor protein Deltex has already been implicated in an alternative Notch signalling pathway that also represses achaete/scute, so Ramain et al. tried inactivating Deltex on an N^Mcd background. This time, the N^Mcd mutant phenotype was rescued, indicating that it was caused by abnormal activation of a Deltex-mediated pathway. Because the N^Mcd phenotype depends on Deltex activation, this pathway must presumably have to be repressed in order for microchaetae to develop. How might this be achieved? A clue came the finding that the N^Mcd alleles produce truncated forms of Notch that lack an intracellular binding site for the Dishevelled protein, which can act as a Deltex antagonist. The authors also argue that Deltex and Su(H) antagonize one another, so the lateral inhibition and Deltex-mediated pathways cannot be active at the same time.

What are the implications of these findings? Ramain et al. suggest that the Deltex-dependent Notch signalling pathway might be active in all neuroectodermal cells early in development, perhaps preventing them from differentiating too early. For a cell to make a fate choice through lateral inhibition, it is necessary first to repress Deltex, and Dishevelled might be one of the factors responsible for this inhibition. This mechanism could be compared to releasing the handbrake on a car; although this allows the car to move, it does not determine where it will go. Similarly, repressing the Deltex-mediated pathway gives cells the freedom to choose their fate, but does not tell them what to become.