The Function And Mechanism Of Alternative Splicing Molecule Eftud2 In Regulating Cerebral Cortex Development

The cerebral cortex,which accounts for more than half of the human brain,is responsible for dealing with complex behaviors such as perception,thought,language,attention,episodic memory and spontaneous movement.During embryonic development,it will be formed according to a series of genetically predetermined molecular and cellular events,and the abnormality of any one of these links will lead to the occurrence of various neurodevelopmental diseases.The nervous system through alternative splicing to achieve cell differentiation,morphogenesis,synaptic formation and plasticity is one of the key regulatory links.However,the function and related mechanism of alternative splicing molecule Eftud2 in neurodevelopment are still unclear.Our previous studies found that Eftud2,the core component of U5 protein encoding splice,was highly expressed in the central nervous system during embryonic development,which suggested that Eftud2 might be involved in the neural development process.In order to further study the mechanism of Eftud2 participating in neural development,this study constructed nerve-specific conditional knockout mice with Cre-loxp strategy to further explore the physiological function of Eftud2 regulating cerebral cortex development and the neurobiological mechanism of Eftud2 gene mutation leading to microcephaly.These findings of this study are as follows:(1)Knockout mice show severe brain developmental defects,such as reduced brain size,thinner cortex,abnormal projection of corpus callosum and disordered migration of neurons;(2)The neural stem cells in cerebral cortex of hGFAP cKO mice began to decrease in proliferation,increase in apoptosis and accompany with aging on embryonic E13.5-E15.5 days.(3)Eftud2 deletion can lead to the shortening of neuronal leading process,which can be partially saved by the re-expressed exogenous Eftud2,but can not be saved by Eftud2 mutant,which indicates that these three sites are the functional sites that Eftud2 plays an important role in the development of mice cerebral cortex.To sum up,our work is to specifically knock out Eftud2 in mouse model to explore the effect of Eftud2 on mouse cerebral cortex development,further expand and extend Eftud2’s understanding of the regulatory mechanism of neurodevelopment,provide neurobiological clues for revealing the occurrence of clinical disease MFDM caused by Eftud2 gene mutation,and provides a new perspective for the diagnosis and treatment of related neurodevelopmental diseases.