A new family of neural wiring receptors across bilaterians defined by phylogenetic, biochemical and structural evidence

The evolution of complex nervous systems was accompanied by the expansion of groups of protein families, most notably cell adhesion molecules, surface receptors and their ligands. These proteins mediate axonal guidance, synapse targeting, and other neuronal wiring-related functions. Recently, members of a set of thirty interacting cell surface proteins belonging to two newly defined families of the immunoglobulin superfamily (IgSF) in fruit flies were discovered to label different subsets of neurons in the brain and ventral nerve cord. They have been shown to be involved in synaptic targeting and morphogenesis, retrograde signaling, and neuronal survival. Here we show that these proteins, denoted as Dprs and DIPs, belong to a family of two and three-Ig domain molecules in bilaterians generally known for neuronal wiring functions. In protostomes, the ancestral Dpr/DIP gene has duplicated to form heterophilic partners, such as Dprs and DIPs, while in deuterostomes, they have evolved to create the IgLON family of neuronal receptors. In support of this phylogeny, we show that IgLONs interact with each other, and that their complexes can be broken by mutations designed using homology models based on Dpr and DIP structures. Similarly, the nematode orthologs ZIG-8 and RIG-5 can form heterophilic and homophilic complexes structurally matching Dpr-DIP and DIP-DIP complexes. The evolutionary, biochemical and structural relationships we demonstrate here provides insights into neural development and the rise of complexity in metazoans.\n\nSignificance StatementCell surface receptors assign and display unique identities to neurons, and direct proper and robust wiring of neurons to create functional neural circuits. Recent work has identified two new classes of receptors in fruit flies, called the Dpr and DIP families with 30 members, which interact in 38 pairwise combinations. These proteins are implicated in neural identity, wiring and survival in many parts of the fly nervous system. Here, using evolutionary, biochemical and structural evidence, we show that Dprs and DIPs are members of an ancient bilaterian family of receptors. Members of this family share functional roles relevant to wiring across species, and are likely crucial in the emergence of the bilaterian nervous systems common to vertebrate and invertebrate animals.