Introduction Genetic technologies provide an opportunity to study the molecular basis of a wide range of hereditary pathologies, including mental disorders. Reproducing of potentially pathogenic genomic variants in cellular and animal models allows establishing their functional significance and possible mechanisms of involvement in the pathogenesis of certain disorders. Methods In this study, a genetic variant of urokinase type plasminogen activator (uPA, gene Plau) was modeled in mice using CRISPR/Cas genome editing tool, enabling a better understanding of the role of this molecule and its associated pathways in brain development. The protease uPA plays an important role in the directed migration of neural progenitors, glial, endothelial and immune cells, it participates in axon guidance and maturation of synaptic connections, activation of growth factors and degradation of the extracellular matrix. To study the contribution of the catalytic function of uPA to brain development, we have created for the first time a mouse line carrying the D277N (rs1243306395) mutation. We assessed social activity, anxiety, memory, problem-solving ability and stress resistance of these mice, as well as histological features of their brains. Results Timely and correct functioning of the Plau gene ensures adequate positioning of crucial cellular components in the developing nervous system. According to bioinformatic calculations, the D277N (corresponds to the human single nucleotide variant rs1243306395) substitution that happens due to C-to-T mutation in the murine Plau gene may impair the catalytic activity of the uPA protein. While retaining their ability to find solutions in the escape test, this mouse line is characterized by high levels of anxiety, impaired social behavior, slowed learning dynamics (spatial memory), and impaired adaptation to stressors. This behavioral pattern can potentially be interpreted as autism spectrum disorder Histological analysis of the brain and cerebral cortex in Plau-D277N mice revealed brain volume enlargement and cortical thickening of approximately 10-15% compared to wild-type mice. Discussion In this study, we draw attention for the first time to the genomic variant rs1243306395 in the Plau gene as a potential cause of autism spectrum disorder and propose the genetically modified Plau-D277N mouse line as a model object for studying the pathogenesis of this disorder. These models can also be used for the development and testing of promising therapeutic approaches and pharmacological agents.
Karagyaur et al. (Wed,) studied this question.