Teneurin-3 Specifies Morphological and Functional Connectivity of Retinal Ganglion Cells in the Vertebrate Visual System

In the vertebrate retina, retinal ganglion cells (RGCs) develop stereotypic dendritic arborization patterns and make specific synaptic connections with amacrine and bipolar cells in the inner plexiform layer (IPL) (Masland, 2012). The formation of such precise connections is critical for the processing of visual information and the generation of feature selectivity in RGCs (Gollisch and Meister, 2010,Wässle, 2004). A key structural characteristic of visual circuits is the organization of connections into precise laminae (Roska and Werblin, 2001,Sanes and Zipursky, 2010). Recent studies have shown that the assembly of neuropil strata in the IPL is regulated by both adhesive (Yamagata and Sanes, 2008) and repulsive transmembrane proteins (Matsuoka et al., 2011). Similarly, such attractive and repulsive cues are also crucial in establishing specific connectivity between RGC axons and their targets in the brain (Osterhout et al., 2011,Xiao et al., 2011). Our understanding of the molecular mechanisms that specify connections within the retina and between the retina and retinorecipient nuclei in the brain, however, is still far from complete. Teneurins (Ten-m/Odz) are a phylogenetically conserved family of type II transmembrane proteins (Tucker et al., 2012,Tucker and Chiquet-Ehrismann, 2006). Their large extracellular domain contains eight epidermal growth factor (EGF)-like repeats, multiple tyrosine and aspartate (YD) repeats and five NHL (NCL-1, HT2A, and Lin-41) repeats, which mediate homophilic recognition and adhesion (Beckmann et al., 2013). In vertebrates, these proteins are encoded by four genes, teneurin 1–4 (also called odz1–4), expressed in distinct and often interconnected regions of the nervous system (Tucker and Chiquet-Ehrismann, 2006). In Drosophila, the role of teneurins in synaptic partner matching and target choice has been elegantly shown in the olfactory system (Hong et al., 2012) and at the neuromuscular junction (Mosca et al., 2012). In mice, teneurins regulate the generation of binocular visual circuits by controlling the development of ipsilaterally projecting RGCs (Dharmaratne et al., 2012,Leamey et al., 2007,Young et al., 2013). However, a role for teneurins in mediating synapse-specific functional wiring in the vertebrate visual system has yet to be demonstrated. Here, we investigate the role of teneurin-3 (hereafter referred to as tenm3) in shaping the morphological and functional connectivity of RGCs in vivo using zebrafish. We report that tenm3 is expressed in RGCs, amacrine cells, and the main retinorecipient target in the brain, the optic tectum. We show that tenm3 knockdown induces stratification and targeting errors of both dendrites and axons in a subset of RGCs. In support of this, we provide evidence showing that orientation-selective, but not direction-selective, responses are impaired in tenm3 morphants, suggesting that tenm3 is involved in wiring subsets of functionally defined visual circuits.