New tricks for an old dog

Notch signalling is involved in cell-fate decisions in many organisms, and the molecular events that underlie these decisions are well established. But no pathway acts in isolation and there have been intriguing reports that another signalling pathway — mediated by Wingless — might interact with Notch signalling. New evidence in support of this cross-talk comes from Ramain et al. who, through their analysis of new dominant Notch alleles, reveal the existence of a novel Notch pathway in Drosophila and show that it is antagonized by Wingless signalling.

Notch, a transmembrane receptor, is best known for mediating lateral inhibition — a mechanism that allows neighbouring cells to adopt one of two different cell fates. Consistent with the function of Notch in preventing neural fate, lateral inhibition through Notch specifies the number and positioning of microchaetae—short sensory bristles — on the adult body of the fly. When Ramain and colleagues characterized several dominant Notch mutants (N^Mcd) that they had identified in a genetic screen for loss of microchaetae, they were surprised to find that the mutant phenotype was independent of the classical lateral inhibition pathway. So how is the Notch signal transduced in microchaetae? Previous reports indicated that the cytoplasmic protein Deltex (Dx) can bind to the intracellular portion of Notch; Ramain et al. showed that mutations in Dx suppress the N^Mcd gain-of-function phenotypes, indicating that this non-canonical Notch pathway requires Dx.

This new microchaetae-repressing function of Notch would be expected to be inhibited in wild-type flies. Dishevelled (Dsh), another component of the Wingless pathway, had been previously reported to interact physically with Notch, and so the authors proposed that Dsh antagonizes the Dx-dependent function of Notch on the adult body. In vivo and in vitro analysis showed not only that Dsh is involved, but also that it binds to the intracellular portion of Notch that is missing in the N^Mcd mutant proteins.

Ramain et al. propose that, in wild-type flies, the newly discovered Dx-dependent pathway acts early to prevent neural-cell differentiation, and cell-fate choice through lateral inhibition occurs only after the Dx-dependent pathway has been blocked by Dsh — allowing microchaetae to develop. More tissues in Drosophila and in vertebrates will need to be examined to determine how widespread the functioning of this new Notch pathway really is.