Mutations in the gene encoding O-GlcNAc transferase lead to embryonic lethality or a severe form of X-linked intellectual disability in humans. This disorder presents with developmental delay, low IQ, and several other developmental defects. To model this disorder, we turned to C. elegans, unique in model organisms in its fully mapped development and in that worms survive without O-GlcNAc. This post-translational protein modification is involved in diverse biological processes including nutrient signaling, signaling, and development. Deletion of the O-GlcNAc transferase gene (
ogt-1) results in C. elegans males with reduced ability to successfully mate. This phenotype likely impacts signaling or development and may provide insights into which pathways are involved in this disorder. Compared to wild-type male controls,
ogt-1 males have a four-fold reduction in mean offspring, with nearly two thirds failing to produce any offspring at all. Fluorescent sperm tracking assays revealed that
ogt-1 males transfer fewer sperm to their mates. We also determined that
ogt-1 males show an increased incidence of developmental defects in male tail structures important to mating. Together, these data suggest a defect in mating behavior is the most likely explanation for the phenotype. In support of this,
ogt-1 males are less likely than wild-type males to initiate mating when presented with mates. Compared with wild-type males,
ogt-1 males are less likely to actively search for mates when isolated from other worms. This indicates these males have an imbalance between mating drive and food-seeking behavior. The genetic amenability of C. elegans allows incorporation of transgenes, which we have exploited to determine the tissue-specific effects of
ogt-1 on the mating phenotype. As a positive control, we injected a wild-type copy of
ogt-1 into deletion worms and demonstrated it was sufficient to rescue both the lost enzymatic activity and male infertility associated with
ogt-1 deletion. Fertility was also rescued by expressing
ogt-1 in a hypodermis-specific manner, which further implicates the development of the male copulatory organ, which is largely derived from the hypodermal lineage. Alternatively, the infertility may arise from disruption of signaling pathways within the hypodermis. This study reveals a crucial role for O-GlcNAc in complex developmental and behavioral processes in the C. elegans male. Genetic and molecular studies will further define the developmental and neuronal mechanisms impacted by O-GlcNAc.