Neuronal and non-neuronal functions of the synaptic cell adhesion molecule, neurexin, in Nematostella vectensis

The transition from diffusion-mediated cell-cell communication to faster and more targeted synaptic signaling in animal nervous systems has long been of interest to evolutionary biologists. Although genome sequencing of early-diverging metazoans has revealed the broad distribution of synapse-related genes among them, synaptic structures have been observed only in Cnidaria, the sister group to Bilateria. How synaptic machinery evolved remains largely unknown. In this study, we investigated the function of neurexins (Nrxns), a core family of presynaptic cell adhesion molecules with critical roles in bilaterian chemical synapses, using the cnidarian model, Nematostella vectensis . Neural Nrxns, named delta-Nrxns, are expressed mainly in neuronal cell clusters that exhibit both peptidergic and classical neurotransmitter signaling. Knockdown of Nrxnδ genes reduced spontaneous peristalsis of N. vectensis polyps. Interestingly, gene knockdown and pharmacological studies suggested that Nrxnδ is involved in glutamate- and glycine-mediated signaling rather than peptidergic signaling. Knockdown of the epithelial Nrxn in N. vectensis revealed a major role in cell adhesion, particularly between ectodermal and endodermal epithelia. Overall, this study provides molecular, functional, and cellular insights into the ancestral, non-neural function of Nrxns, as well as key information for understanding how and why this family of cell adhesion molecules was recruited to synaptic machinery.