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Many of the immunoglobulin superfamily (IgSF) molecules play pivotal roles in cell communication. The Sidekick (Sdk) gene, first described in Drosophila, encodes the single-pass transmembrane protein, Sdk, which is one of the largest among IgSF membrane proteins. Sdk first appeared in multicellular animals during the Precambrian age and later evolved to Sdk1 and Sdk2 in vertebrates by gene duplication. In flies, a single Sdk is involved in positioning photoreceptor neurons and their axons in the visual system and is responsible for dynamically rearranging cell shapes by strictly populating tricellular adherens junctions in epithelia. In vertebrates, Sdk1 and Sdk2 are expressed by unique sets of cell types and distinctively participate in the formation and/or maintenance of neural circuits in the retina, indicating that they are determinants of synaptic specificity. These functions are mediated by specific homophilic binding of their ectodomains and by intracellular association with PDZ scaffold proteins. Recent human genetic studies as well as animal experiments implicate that Sdk genes may influence various neurodevelopmental and psychiatric disorders, such as autism spectrum disorders, attention-deficit hyperactivity disorder, addiction, and depression. The gigantic Sdk1 gene is susceptible to erratic gene rearrangements or mutations in both somatic and germ-line cells, potentially contributing to neurological disorders and some types of cancers. This review summarizes what is known about the structure and roles of Sdks.

Processes of >100 types of interneurons (bipolar and amacrine cells) and projection neurons (retinal ganglion cells, RGCs) form specific and stereotyped patterns of connections in the inner plexiform layer (IPL) of the mouse retina. Four closely related homophilic immunoglobulin superfamily recognition molecules (Sidekick [Sdk] 1, Sdk 2, Dscam, and DscamL1) have been shown to play roles in patterning neuronal arbors and connections in chick retina, and all but Sdk1 have been shown to play related roles in mice. Here, we compare patterns of Sdk1 and Sdk2 expression in mouse retina and use genetic methods to assess roles of Sdk1. In adult retina, 3 neuronal types express sdk1 but not sdk2 at detectable levels, 5 express sdk2 but not sdk1 and 3 express both. Patterns of gene expression and protein localization at or near synapses are established during the first postnatal week. Dendrites of amacrine cells and RGCs that express sdk1 but not sdk2 arborize in the same narrow stratum in the center of the IPL. In the absence of Sdk1, this laminar restriction is degraded. Overexpression of sdk1 in developing cells that normally express sdk2 reorients their dendrites to resemble those of endogenously Sdk1-positive cells, indicating that Sdk1 plays an instructive role in patterning the IPL. Sdk1 fails to affect arbors when introduced after they are mature, suggesting that it is required to form but not maintain laminar restrictions. The effect of ectopically expressed sdk1 requires the presence of endogenous Sdk1, suggesting that the effect requires homophilic interactions among Sdk1-positive neurites. Together with previous results on Sdk2, Dscam, DscamL1, as well as the related Contactins, our results support the idea that an elaborate immunoglobulin superfamily code plays a prominent role in establishing neural circuits in the retina by means of tightly regulated cell type-specific expression and homophilically restricted intercellular interactions.

Classical cadherins, a set of ~20 related recognition and signaling molecules, have been implicated in many aspects of neural development, including the formation and remodeling of synapses. Mechanisms underlying some of these steps have been studied by expressing N-cadherin (cdh2), a Type 1 cadherin, in heterologous cells, but analysis is complicated because widely used lines express cdh2 endogenously. We used CRISPR-mediated gene editing to generate a Human embryonic kidney (HEK)293 variant lacking Cdh2, then compared the behavior of rodent cortical and hippocampal neurons co-cultured with parental, cdh2 mutant and cdh2-rescued 293 lines. The comparison demonstrated that Cdh2 promotes neurite branching and that it is required for three synaptic organizers, neurologin1 (NLGL1), leucine-rich repeat transmembrane protein 2 (LRRtm2), and Cell Adhesion Molecule 1 (Cadm1/SynCAM) to stimulate presynaptic differentiation, assayed by clustering of synaptic vesicles at sites of neurite-293 cell contact. Similarly, Cdh2 is required for a presynaptic organizing molecule, Neurexin1β, to promote postsynaptic differentiation in dendrites. We also show that another Type I cadherin, Cdh4, and a Type II cadherin, Cdh6, can substitute for Cdh2 in these assays. Finally, we provide evidence that the effects of cadherins require homophilic interactions between neurites and the heterologous cells. Together, these results indicate that classical cadherins act together with synaptic organizers to promote synaptic differentiation, perhaps in part by strengthening the intracellular adhesion required for the organizers to act efficiently. We propose that cadherins promote high affinity contacts between appropriate partners, which then enable synaptic differentiation.