Homeodomain protein codes specify neuronal diversity in the first ganglion of the Drosophila visual system

Recent advances in single-cell transcriptional profiling have enabled us to map diverse neuron types across Drosophila , mice, and even human brains, yet we still lack a mechanistic understanding of how these neuron types arise in the brain and expand during evolution. We identified homeodomain transcription factor (HDTF) codes in newborn neurons that specify the five neuron types (L1-L5) in the Drosophila lamina, the first ganglion of the visual system. Specifically, we discovered that the pan-lamina HDTF Scro is required for lamina progenitors to exit proliferation and differentiate into lamina neurons. Furthermore, we showed that specific HDTFs are expressed in distinct newborn neurons and specify different lamina neuron types: Zfh1 for L1 and L3, Dve for L2, and Bsh for L4 and L5. Intriguingly, we found that the loss of both Dve and Bsh causes L2, L4, and L5 neurons to revert to L1 and L3 neuron types, potentially representing ancestral lamina neuron types. HDTFs are evolutionarily conserved and broadly expressed in brains across species. Based on these findings, we propose a model in which distinct HDTFs in newborn neurons specify different neuron types in the brain and have been utilized to expand neuron diversity during evolution.