Csgalnact1, which encodes chondroitin sulfate N-acetylgalactosaminyltransferase 1, is a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate [2,3,6]. It initiates chondroitin sulfate (CS) chain biosynthesis on the GAG-protein linker region tetrasaccharide [6]. CS, a major component of proteoglycans in the extracellular matrix, is involved in numerous biological processes, such as synaptic plasticity in the brain and the synthesis of connective tissues [1,4].

Gene knockout mouse models have provided crucial insights into Csgalnact1's functions. T1KO mice (lacking Csgalnact1) show extensive axon regeneration following spinal cord injury and loss of onset of ocular dominance plasticity, suggesting its importance in neuronal plasticity and axon regeneration [1]. Biochemically, the loss of this enzyme reduces CS amount by about 50% in various brain regions, leading to abnormal behaviors in tests like the open-field test, acoustic startle response, and social preference, indicating its role in regulating CS-dependent perineuronal nets (PNNs) [4]. In addition, CSGalNAcT1-KO mice have milder symptoms in experimental autoimmune encephalomyelitis compared to wild-type mice, suggesting CS's contribution to the induction phase of this disease [5]. Diabetic T1KO mice are more resistant to diabetic neuropathy, with more stable pericyte-endothelial cell interactions and less up-regulated Smad2/3 phosphorylation in the transforming growth factor β signaling pathway [7]. In humans, biallelic loss-of-function mutations in Csgalnact1 cause a mild skeletal dysplasia with features like joint hypermobility, axial malalignment, and advanced bone age [2,3,6].

In conclusion, Csgalnact1 plays essential roles in neuronal plasticity, axon regeneration, immune-related neurological diseases, and skeletal development. The study of Csgalnact1 KO mouse models has significantly advanced our understanding of its functions in these disease-related biological processes, providing potential insights for treating related disorders.