Teneurins Are SPARCL1 Receptors

Extensive experiments document that SPARCL1, a secreted protein that is produced primarily by astrocytes in brain and endothelia throughout the body and that is also known as Hevin, enhances synapse formation. However, the mode of action of SPARCL1 at synapses remains unclear owing to divergent results in the literature. Here, we use cultured neurons from newborn male and female mouse embryos to show that the C-terminal follistatin-like and Ca2+-binding domains of SPARCL1, which account for only 35% of the total SPARCL1 sequence, are sufficient to potently enhance synapse numbers. SPARCL1 acts at nanomolar concentrations at which SPARCL1 does not robustly bind to neurexins, neuroligins or neurexin/neuroligin complexes but avidly interacts with all teneurins. Strikingly, the follistatin-like domain of SPARCL1 on its own strongly binds to teneurins but is unable to stimulate synapse formation. Only when combined with the SPARCL1 Ca2+- binding domain does the follistatin-like domain induce synapses, suggesting that SPARCL1 enhances synapse numbers by binding to teneurins via its C-terminal follistatin-like domain and by activating synapse formation via its Ca2+-binding domain. SIGNIFICANCE STATEMENTSPARCL1 (also known as Hevin) is a synaptogenic factor that is produced primarily by astrocytes in brain, and that enhances synapse formation. How SPARCL1 acts at synapses, however, remains unclear because divergent results describe its binding partners at synapses and the sequences involved in its synaptogenic activity remain unclear. In the present study, we show that SPARCL1 avidly binds to the presynaptic teneurins adhesion molecules, that this binding is mediated by its small follistatin-like domain, and that its synaptogenic activity requires both its follistatin-like and its Ca2+-binding EC domains. Thus, our results suggest that SPARCL1 is recruited to developing synapses by binding of its follistatin-like domain to teneurins and then induces synapse assembly via its Ca2+-binding domain.