Am J Physiol Gastrointest Liver Physiol. 2025 May 6. doi: 10.1152/ajpgi.00408.2024.
Contribution of neuroligin and neurexin alternative splicing to the establishment of enteric neuronal synaptic specificity
Fabien D’AutrĂ©aux1,2, Alcmène Chalazonitis1, Dena Arumugam1, Timothy Gershon3, Michael D Gershon1
Affiliations
1Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
2UniversitĂ© CĂ´te d’Azur, CNRS, Inserm, iBV, Institut de Biologie Valrose, 06108 Nice, France.
3Department of Pediatrics, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA.
 Abstract
The enteric nervous system (ENS) is unique among components of the peripheral nervous system due to its complexity in structure and neurotransmitter phenotype diversity. In this complexity, the ENS resembles the CNS. Although the ENS is derived from the neural crest rather than the neural tube, similar mechanisms may generate complex connectivity in both the ENS and the CNS. Neuroligins and neurexins are cell adhesion molecules that participate in regulating CNS synaptogenesis. We investigated whether these molecules also play a role in establishing enteric synapses. We found that neuroligins and neurexins were expressed in mouse, rat, and human gut. Transcripts of both type of molecule were extensively spliced in the bowel during fetal and adult life. When transfected into non-neuronal cells, neuroligins and neurexins were sufficient to recruit respectively, presynaptic and postsynaptic elements. Engineered soluble neurexin, which interferes with endogenous neurexin-neuroligin binding, inhibited enteric synapse formation/stabilization and recruitment of neurotransmitter receptors. Finally, we demonstrated that alternative splicing of neuroligin and neurexin contributes to ENS synaptic specificity. Some isoforms preferentially induced cholinergic synapses, whereas others promoted serotonergic synaptogenesis.