The teneurins, also known as Ten-m/Odz, are highly conserved type II transmembrane glycoproteins widely expressed throughout the nervous system. Functioning as dimers, these large cell-surface adhesion proteins play a key role in regulating neurodevelopmental processes such as axon targeting, synaptogenesis and neuronal wiring. Synaptic specificity is driven by molecular interactions, which can occur either in a trans-homophilic manner between teneurins or through a trans-heterophilic interaction across the synaptic cleft between teneurins and other cell-adhesion molecules, such as latrophilins. The significance of teneurins interactions during development is reflected in the widespread expression pattern of the four existing paralogs across interconnected regions of the nervous system, which we demonstrate here via in situ hybridization and the generation of transgenic BAC reporter lines in zebrafish. Focusing on the visual system, we will also highlight the recent developments that have been made in furthering our understanding of teneurin interactions and their functionality, including the instructive role of teneurin-3 in specifying the functional wiring of distinct amacrine and retinal ganglion cells in the vertebrate visual system underlying a particular functionality. Based on the distinct expression pattern of all teneurins in different retinal cells, it is conceivable that the combination of different teneurins is crucial for the generation of discrete visual circuits. Finally, mutations in all four human teneurin genes have been linked to several types of neurodevelopmental disorders. The opportunity therefore arises that findings about the roles of zebrafish teneurins or their orthologs in other species shed light on the molecular mechanisms in the etiology of such human disorders.
Synaptic specificity during neurodevelopment is driven by combinatorial interactions between select cell adhesion molecules expressed at the synaptic membrane. These protein–protein interactions are important for instructing the correct connectivity and functionality of the nervous system. Teneurins are one family of synaptic adhesion molecules, highly conserved and widely expressed across interconnected areas during development. These type-II transmembrane glycoproteins are involved in regulating key neurodevelopmental processes during the establishment of neural connectivity. While four teneurin paralogues are found in vertebrates, their subcellular distribution within neurons and interaction between these different paralogues remains largely unexplored. Here we show, through fluorescently tagging teneurin paralogues, that true to their function as synaptic adhesion molecules, all four paralogues are found in a punctate manner and partially localised to synapses when overexpressed in neurons in vitro. Interestingly, each paralogue is differentially distributed across different pre- and post-synaptic sites. In organotypic cultures, Tenm3 is similarly localised to dendritic spines in CA1 neurons, particularly to spine attachment points. Furthermore, we show that the intracellular domain of teneurin plays an important role for synaptic localisation. Finally, while previous studies have shown that the extracellular domain of teneurins allows for active dimer formation and transsynaptic interactions, we find that all paralogues are able to form the full complement of homodimers and cis-heterodimers. This suggests that the combinatorial power to generate distinct molecular teneurin complexes underlying synaptic specificity is even higher than previously thought. The emerging link between teneurin with cancers and neurological disorders only serves to emphasise the importance of further elucidating the molecular mechanisms of teneurin function and their relation to human health and disease.
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