The C. elegans nervous system contains a diverse array of neurons with completely mapped cell lineages and well understood functions. For example, the BAG neurons help worms sense oxygen and carbon dioxide, and mediate behavioural responses via neurotransmitter release to interneurons. The ETS-5 transcription factor is a ‘terminal selector’ for BAG fate, but how ets-5 expression is restricted to BAG neurons to carry out this function has been unclear. Now, Julia Brandt, Mary Rossillo and colleagues shed light on this problem. Beginning with a mutagenesis screen, the authors isolated a mutation in vab-3 (the worm homolog of Pax6) that specifically affects the long isoform of the gene and leads to ectopic expression of BAG fate. The long vab-3 isoform is specifically excluded from BAG cells, while a short homeodomain-only isoform is expressed in them, indicating that the long isoform acts to suppress BAG fate in non-BAG cells. Ectopic BAG neuron fate occurs via altered ets-5 expression in non-BAG cells, and a conserved pathway of VAB-3 partners is involved in the regulation of ets-5 expression (although this regulation is likely to be indirect). In contrast, disruption of short isoform function leads to reduced expression of BAG-specific genes and defective carbon dioxide avoidance. Thus, expression of a terminal selector in development is regulated by two isoforms of a single gene that have opposing inhibitory and activating functions.
