Role of ciliopathy gene, TMEM138 in adult neurogenesis and cognitive deficit

Abstract

Joubert syndrome is caused by mutations in Tmem138 gene involving the vesicular transport to primary cilia and characterized by cognitive dysfunctions. It has been unknown how the dysfunction of ciliary proteins leads to cognitive abnormalities. In this paper, I confirmed that transgenic mice that specifically eliminated the Tmem138 gene in cortex and hippocampus did not produce primary cilia, similar to ciliopathy patients, and had impaired hippocampal-specific learning and memory, which was caused by decreased adult neurogenesis. This is because more apoptotic cells are found in disease model mouse than in control mouse, which was confirmed in fibroblasts of Joubert syndrome patients as well as mice. Because primary cilium is produced from basal bodies based on centrosomes, formation and disassembly are linked to the cell cycle, and ciliary proteins affect not only cilia formation and maintenance but also somatic cell division. In the fibroblasts of patients with Joubert syndrome, it showed many gamma-H2AX-expressing cells that have gene instability, indicating that gene instability was increased due to a decrease in the ciliary protein Tmem138. This resulted in increased p53 expression in the hippocampus of this disease model mouse, and memory deficiency was recovered when p53 expression was reduced through RNAi technology. These results suggest that p53-dependent interference of adult neurogenesis may explain a mechanism of cognitive dysfunctions found in ciliopathies.