Endocrine Abstracts

Obesity is a growing public health concern, with genetic factors significantly influencing risk. Genetic variants in the hypothalamic melanocortin pathway, which regulates satiety through pro-opiomelanocortin (POMC) neurons, are frequently implicated in obesity. Plexin A4 (PLXNA4), a receptor expressed on POMC neurons, regulates cytoskeletal remodeling and maintains structural circuit integrity. Loss-of-function mutations in PLXNA4 impair axonal growth and have been linked to severe obesity, potentially through disrupted development of hypothalamic satiety circuits. Additionally, PLXNA4 variants are associated with neuropsychiatric traits, including anxiety. However, PLXNA4’s specific role in the development of these conditions remains largely unexplored. Zebrafish are tractable models for investigating hypothalamic maturation, as their caudal hypothalamus (cH), containing POMC, serotonergic, and dopaminergic neurons, is involved in both satiety regulation and anxiety-like behaviours. Consequently, the cH may serve as a nexus for PLXNA4’s dual functionality in these processes. This study compared neurodevelopmental changes in the cH of plxna4 mutants and wild-type controls using immunofluorescence to assess neuronal populations at 5, 8, and 14 days post-fertilization (dpf). Anxiety-like behaviour was evaluated using a thigmotaxis assay, measuring the tendency of zebrafish to remain near the walls of their well in response to paramecia, reflecting a more anxious state. plxna4 mutants exhibited disrupted neuronal development, particularly in POMC and serotonergic populations. At 14 dpf, mutants showed a 482.8µm reduction in mean total POMC neurite length (P = 0.033), and a 1,584.8µm² decrease in serotonin-positive area (P < 0.0001). Dopaminergic neurons displayed a milder reduction, with a 742.8 µm² difference (P = 0.38) by 14 dpf. Behaviourally, plxna4 mutants demonstrated increased thigmotaxis, consistent with elevated anxiety-like responses. These findings indicate that PLXNA4 loss impairs hypothalamic neurogenesis, offering insight into the shared genetic basis of obesity and anxiety. This work establishes a foundation for future research into PLXNA4’s pleiotropic roles in neurodevelopment and metabolic-psychiatric comorbidity.