Transcriptome profiling of neurexin- and neuroligin-deficient Caenorhabditis elegans reveals pathways underlying developmental and behavioral dysfunction

Abstract

Neurexins and neuroligins are evolutionarily conserved synaptic adhesion molecules that play essential roles in synapse formation and neural circuit function, with mutations linked to neurodevelopmental disorders such as autism. Here, we combined whole-transcriptome sequencing with phenotypic characterization to define the molecular consequences of neurexin and neuroligin deficiency in Caenorhabditis elegans. Young adult worms carrying allele-specific loss-of-function mutations in nrx-1 (ok1649 and tm1961) or nlg-1 (ok259 and tm474), orthologues for human NRXNs or NLGNs, respectively, were subjected to RNA sequencing and compared with wild-type animals. Mutant strains exhibited impaired growth, altered locomotor activity, increased social aggregation, and reduced ventral nerve cord neuronal integrity. Transcriptomic analysis revealed extensive gene-expression changes, particularly in the nrx-1 (tm1961) allele, with dysregulation of genes involved in cuticle development, neuronal signaling, protein homeostasis, innate immunity, mitochondrial organization, and transcriptional regulation. Gene Ontology and KEGG enrichment analyses identified significant perturbations in developmental, metabolic, stress-response, translational, and synaptic pathways. Together, these findings demonstrate that disruption of neurexin–neuroligin signaling drives transcriptional reprogramming that extends beyond synaptic dysfunction, linking molecular alterations to developmental, behavioral, and neuromorphological abnormalities.