Accurate axonal pathfinding relies on the tightly regulated expression of guidance cues and their receptors, but the links between transcriptional regulators and downstream guidance factors are poorly understood. Genetically amenable Drosophila motoneurons provide an ideal system for analysing the control of guidance receptor expression. It is known that two transcription factors, Even-skipped (Eve) and Grain (Grn) are expressed in the aCC and RP2 motoneurons, and that projection of these neurons to the muscle requires the Netrin receptor Unc-5. Now, Juan-Pablo Labrador and colleagues dissect out the relationships between these factors (). The researchers find that Eve and Grn independently promote Unc-5 transcription, and that both are required to generate sufficient Unc-5 expression for proper pathfinding – likely via an enhancer element in unc-5 intron 5. Overexpression of both Eve and Grn in another motoneuron population induces ectopic Unc-5 and hence axonal redirection. Thus, the combinatorial effects of these two transcription factors together direct expression of the key guidance receptor, and so define the axon’s path.
