USP6,a Hominoid-specific Gene,regulates Synaptic And Cognitive Function Through Deubiquitylating NMDA Receptors

Humans have shown higher cognitive abilities including learning memory and language communication than other mammal species.The basis of human intelligence has been attributed to expanded cerebral cortex,increased neuronal number and the higher complexity of neuronal connections in the human brain.Genetic factors play an important role in brain evolution,some new genes generated during human evolution including ARHGAP2C,TBC1D3,TMEM14B,NOTCH2NL and SRGAP2C,are involved in human brain development and are believed to be closely related to brain evolution.But the effects of genetic factors on the evolution of the human nervous system and intelligence remain unclear.The exploration of new genes or functional mutations generated during human-lineage evolution will help us to understand the mechanism of human brain evolution.Ubiquitination specific protease 6(USP6)is generated by the rearrangement of TBC1D3 and USP32 gene,and only appears in hominoid animals(including orangutans and humans).Clinical studies have shown that patients with the deletion of the USP6 gene caused by chromosome rearrangement suffer from mental retardation or language impairment.However,the neurological function of the USP6 remains unclear.In this study,the role of USP6 in the nervous system was investigated through the methods of tissue morphology,animal behavior,cellular and molecular biology.The major research results included as following.(1)This project investigated the expression of USP6 in human brain and found that the expression of USP6 in adult brain was significantly higher than that in fetal brain tissue.(2)USP6 transgenic mice under the control of Camk2a promoter(Camk2a-USP6)were constructed by gene targeting technology.Behavioral studies showed that the ability of learning memory and language communication of Camk2a-USP6 mice were significantly enhanced.(3)USP6 transgenic mice under the control of Nestin promoter(Nestin-USP6)were constructed by gene targeting technology.Morphological experiments showed that the function of USP6 in development of fetal brain was different with its homologous gene TBC1D3,and USP6 would not induce cortical folding and cortical thickening by affecting the proliferation of neural precursor cells.(4)High-throughput proteomic analysis of ubiquitinated proteins identified several synaptic related proteins with potential roles of USP6,including NMDA receptors.Futhermore,We found that USP6 is a new regulatory factor for ubiquitination and degradation of NMDA receptors.USP6 specifically regulates NMDA receptors,but has no effect on AMPA receptors.In addition,USP6 homologous genes TBC1D3 and USP32 have no significant effect on NMDA receptor expression.In conclusion,our study showed that the hominoid gene USP6 plays a key role in learning memory by regulating the stability of NMDA receptors.In this paper,We deeply studied the function of USP6 in the nervous system,and identified new regulatory mechanisms of NMDA receptors and learning memory,which will be helpful for us to understand the effects of genetic factors on the evolution of human nervous system and explore potential targets for the treatment of mental disorders.