While the small ∼45 kDa intracellular domain is less conserved than the extracellular region ( Minet et al., 1999 Nunes et al., 2005), it nevertheless shows up to 70% sequence similarity between orthologues ( Scholer et al., 2015). Structurally, the teneurins are large proteins of around 300 kDa with a small N-terminal intracellular domain, a single span transmembrane domain, and a large C-terminal extracellular region ( Rubin et al., 1999 Tucker and Chiquet-Ehrismann, 2006 Jackson et al., 2018 Li et al., 2018). There is a high degree of conservation between paralogues, with 58–70% sequence identity between human teneurin-1 to -4 alone ( Jackson et al., 2018). While only one teneurin gene has been identified in most invertebrates, insects have two paralogues ( Tucker et al., 2012) and four teneurin paralogues are present in vertebrates ( Mosca, 2015). Subsequent studies showed they are highly expressed across both the developing and adult nervous systems, particularly in interconnected regions ( Oohashi et al., 1999 Cheung et al., 2019), reflecting a significant role in mediating basic neurodevelopmental processes, such as cell migration, axonal guidance, and synaptic partner matching ( Drabikowski et al., 2005 Leamey et al., 2008 Hong et al., 2012 Berns et al., 2018 Del Toro et al., 2020 Pederick et al., 2021). While many cell adhesion molecules are implicated in this process, the teneurin family of type II transmembrane glycoproteins have been shown to be key mediators of intercellular signalling during development in both vertebrates and invertebrates.Īlso known as Tenm/Odz, the teneurins were originally discovered in the early 1990s in Drosophila as tenascin-like molecule accessory (tena) and tenascin-like molecule major (tenm) ( Baumgartner and Chiquet-Ehrismann, 1993 Baumgartner et al., 1994 Levine et al., 1994). Protein interactions at the synaptic membrane play a pivotal role in driving synaptic specificity, for example, through cell adhesion molecules interacting in a combinatorial manner to generate diverse cellular interactions. Much research has been done on trying to unravel these complex mechanisms and pathways, focusing on different aspects including molecular, structural or activity-related processes. The formation of precise synaptic connections between neurons during development is a fundamental process which ultimately dictates the correct functionality of the nervous system. 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. This suggests that the combinatorial power to generate distinct molecular teneurin complexes underlying synaptic specificity is even higher than previously thought. 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. Furthermore, we show that the intracellular domain of teneurin plays an important role for synaptic localisation. In organotypic cultures, Tenm3 is similarly localised to dendritic spines in CA1 neurons, particularly to spine attachment points. Interestingly, each paralogue is differentially distributed across different pre- and post-synaptic sites. 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. While four teneurin paralogues are found in vertebrates, their subcellular distribution within neurons and interaction between these different paralogues remains largely unexplored. These type-II transmembrane glycoproteins are involved in regulating key neurodevelopmental processes during the establishment of neural connectivity. Teneurins are one family of synaptic adhesion molecules, highly conserved and widely expressed across interconnected areas during development. These protein–protein interactions are important for instructing the correct connectivity and functionality of the nervous system. Synaptic specificity during neurodevelopment is driven by combinatorial interactions between select cell adhesion molecules expressed at the synaptic membrane. 2MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom.1Centre for Developmental Neurobiology, King’s College London, London, United Kingdom.Angela Cheung 1 Greta Schachermayer 1 Aude Biehler 1 Amber Wallis 1 Mégane Missaire 1 Robert Hindges 1,2*
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