Sdk1 has also been shown to be involved in the pathology of focal segmental glomerulosclerosis and HIV-associated neuropathy ( Kaufman et al., 2004, 2007, 2010). Since all 10 of these IgSF molecules are also expressed by neuronal subsets throughout the central nervous system ( Yamakawa et al., 1998 Agarwala et al., 2001 Shimoda and Watanabe, 2009 Stoeckli, 2010 Yamagata and Sanes, 2012a), similar interactions may mediate connectivity in multiple brain regions. These results have led to the hypothesis that IgSF-mediated homophilic interactions bias synaptic connectivity in favor of appropriate partners, thus generating information processing circuits in the retina. In one case, the specific connectivity of an interneuron type (vesicular glutamate transporter 3-positive amacrine cells or VG3-ACs) to a specific RGC type (W3B-RGCs) depends upon expression of Sdk2 in both cell types: transmission from VG3-ACs to W3B-RGCs fails in Sdk2 mutants and the RGCs no longer respond to their canonical visual feature ( Krishnaswamy et al., 2015). In mice, Sdk1, Sdk2, Dscam, DscamL1 and CNTN5 mutants each exhibit specific defects in arborization and connectivity within the IPL ( Fuerst et al., 2008, 2009 Krishnaswamy et al., 2015 Peng et al., unpublished). In chick, Sdk, Dscam and CNTN family proteins are present as interneuron-RGC synapses form, and both knockdown and over-expression experiments show that they are necessary and sufficient for directing neural processes to particular sublaminae in the IPL ( Yamagata et al., 2002 Yamagata and Sanes, 2008, 2012a). Studies in chicks and mice have revealed that defined interneuron and RGC subtypes express one or more of 10 closely related IgSF members: Sdk1, Sdk2, Dscam, DscamL1, and Contactins 1–6 (CNTNs 1–6) in largely non-overlapping patterns ( Yamagata et al., 2002 Yamagata and Sanes, 2008, 2012a Fuerst et al., 2008, 2009 Shekhar et al., 2016). Some aspects of this specific connectivity appear to be mediated by recognition molecules of the immunoglobulin superfamily (IgSF). Synapses between these interneurons and RGCs form in the inner plexiform layer (IPL) of the retina, with arbors of each specific neuronal subtype confined to one, or a few, of the approximately 10 sublaminae ( Roska and Werblin, 2001 Sanes and Zipursky, 2010). Highly stereotyped patterns of connectivity between the ~70 types of interneurons and ~30 types of RGCs render the latter sensitive to specific visual features such as motion or edges ( Sanes and Masland, 2015). In the vertebrate retina, light-sensitive photoreceptors synapse on interneurons these interneurons process the information and pass it to retinal ganglion cells (RGCs), which send it to the brain ( Masland, 2012). We suggest that competition between cis and trans interactions provides a novel mechanism to sharpen the specificity of cell-cell interactions. Sdk1/Sdk2 recognition specificity is encoded across Ig1–4, with Ig1–2 conferring the majority of binding affinity and differential specificity. Structure-guided mutagenesis results show that this canonical dimer is required for both Sdk-mediated cell aggregation (via trans interactions) and Sdk clustering in isolated cells (via cis interactions). These Ig1–4 horseshoes interact in a novel back-to-back orientation in both homodimers through Ig1:Ig2, Ig1:Ig1 and Ig3:Ig4 interactions. Here we report crystal structures of Sdk1 and Sdk2 ectodomain regions, revealing similar homodimers mediated by the four N-terminal immunoglobulin domains (Ig1–4), arranged in a horseshoe conformation. Sdks mediate cell-cell adhesion with homophilic specificity that underlies their neuronal targeting function. Sidekick (Sdk) 1 and 2 are related immunoglobulin superfamily cell adhesion proteins required for appropriate synaptic connections between specific subtypes of retinal neurons.
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