Cardiac defects and Wnt/β-catenin signalling impairment in lgals3a zebrafish mutants

Arrhythmogenic cardiomyopathy (AC) is an inherited disease, mostly caused by mutations in genes that encode desmosomal proteins. However, recent evidence suggests a potential causative role played by reduced Galectin-3 expression in early AC onset. Thereby, we aimed to characterise a zebrafish line with a frameshift mutation in the gene encoding for Galectin-3 (lgals3a). Using a specific transgenic zebrafish line and qPCR analysis, we demonstrated that canonical Wnt/β-catenin signalling, a pathway frequently dysregulated in AC, is significantly suppressed in lgals3a -/- mutant larvae, similar to what observed in other AC models. The expression of Desmoplakin protein was also found to be reduced by Western blot analysis. Moreover, these larvae exhibited developmental defects and morphological alterations in their cardiac region with a 35% penetrance, among which we revealed cardiac chamber dilation, pericardial effusion and bradycardia phenotype. The dilation of the heart was maintained in 1-year-old mutant zebrafish. Lgals3a mutation also induced cell death and inflammatory response in the larval cardiac region. In parallel, these animals showed ~17% decrease in their life expectancy compared to their WT counterparts. In summary, the Lgals3a-KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable model to study Galectin-3 as a remarkable modulator of Wnt/β-catenin signalling and AC-like phenotypes.