Functional integration of "undead" neurons in the olfactory system

Programmed cell death (PCD) is widespread during nervous system development, eliminating up to half of the neurons in certain regions of mammalian brains. PCD can serve to counterbalance the surpluses of neural production, and contribute to the formation of correct connectivity. Here we show that cells normally fated to die also represent a reservoir of potential neurons that could contribute to neural circuit evolution. We used as a model the Drosophila peripheral olfactory system, whose lineages exhibit extensive, stereotyped patterns of PCD. Inhibition of developmental PCD is sufficient to generate many new cells in the antenna that express neural markers. Electrophysiological recordings from these 9undead9 neurons9 sensory dendrites reveal that they exhibit basal and odour-evoked activity similar to wild-type neurons. Transcriptomic and in situ analyses demonstrate that undead antennal neurons express a subset of olfactory receptor genes, including those expressed naturally in other olfactory organs in adults and larvae. Intriguingly, this subset is enriched for relatively young gene duplicates that are normally co-expressed in wild-type neurons. Undead neurons therefore provide a potential cellular substrate to allow the switch of receptors between sensory organs or life stages, as well as accommodate recently-generated receptor genes. Finally, we show that undead neurons can extend axons to novel regions in the primary olfactory centre in the brain, where they may form synaptic connections with second order projection neurons. These data indicate that undead neurons retain a molecular programme that enables their functional integration into the extant olfactory system, raising the possibility that alterations in PCD patterning during evolution is a simple way to generate new sensory pathways. Consistently, comparative analysis of homologous olfactory lineages across the drosophilid phylogeny revealed multiple independent examples where the presence of an additional neuron is consistent with evolutionary fate changes from PCD to a functional olfactory sensory neuron.