By identifying 42 orthologous amacrine cell types across 24 vertebrates, this study overturns the assumption that retinal inhibitory diversity is idiosyncratic, revealing a deep evolutionary logic that anchors cross-species neuroscience and disease modeling.
Integration of single-cell transcriptomic atlases across 24 vertebrate species reveals that amacrine cell diversity comprises 42 molecularly conserved orthologous types that originated over 500 million years ago in basal vertebrates, with GABAergic amacrine cells and retinal ganglion cells sharing common evolutionary ancestry from an AC-RGC hybrid precursor while glycinergic amacrine cells diverged earlier, and amacrine cell diversity scales linearly with retinal ganglion cell diversity across species indicating coordinated circuit evolution.
Amacrine cells (ACs) comprise a heterogeneous class of inhibitory neurons in the vertebrate retina, exhibiting morphological and functional complexity rivaling that of cortical interneurons. Here, we integrate single-cell and single-nucleus transcriptomic atlases from 24 vertebrate species to reconstruct the evolutionary origins of this extreme diversity. We identify 42 orthologous AC types (oACs), most of which exhibit a one-to-one correspondence across amniotes and, in many cases, across vertebrates. While core molecular identities are conserved, AC types vary in abundance and gene expression across species, likely reflecting adaptations to distinct visual ecologies. AC diversity scales with that of retinal ganglion cells (RGCs), indicative of co-evolution. Finally, we suggest that ACs arose from an AC-RGC hybrid precursor, with glycinergic ACs diverging early in vertebrate evolution, followed by a bifurcation between RGCs and GABAergic ACs. Together, these findings establish a unified evolutionary framework for understanding the diversity, development, and function of a class of inhibitory neurons across vertebrates.