Drosophila and human transglutaminases are partially interchangeable, revealing evolutionary conserved roles in brain development

Abstract Transglutaminases (TGs) are a family of enzymes characterized by their calcium-dependent transamidation activity. In higher mammals, TG2 is the family member with the highest expression in the brain. Intriguingly, TG2 KO mice show no major neurodevelopmental abnormalities, which might be explained by compensation from the other members of the TG family also expressed in mammalian CNS. Thus, simpler animal models are likely better suited to study the contribution of TGs to brain formation and operation. The fruit fly Drosophila melanogaster contains a single TG gene ( dTg ), but its contribution to brain development and function remains poorly understood. Here, we show that dTg mutants display structural defects in the mushroom body (MB), an important associative area in Drosophila CNS, and in brain dopaminergic neurons both in vivo and in vitro. Furthermore, dTG-deficient animals show altered fly locomotion and strong asocial-like phenotype, two phenotypes associated with dopaminergic dysfunction. Consistent with these findings, brain transcriptomic experiments reveal changes in the expression of several genes associated with neurogenesis and neurodevelopment in dTG-deficient animals. Interestingly, expression of human TG6 (hTG6) under control of the endogenous dTg promoter rescues the social phenotype and the dopaminergic neurons loss. This manipulation partially reverts the changes in gene expression, and the motor defects. The partial reversion of phenotypes by hTG6 is consistent with a partial rescue of the epigenetic mark histone dopaminylation. Our data support the evolutionary conservation of TG functions across species and that TGs contribute to the maturation of brain neurons and circuits.