Cell Reports . . . A collaborative study by Tang Wei/King Nai-ho-King reveals the mechanism by which genetic mutations cause autism.

Neurodevelopmental disorders are caused by central nervous system abnormalities, including autism spectrum disorders, schizophrenia, depression, mental retardation, epilepsy, etc.among them, autism spectrum disorders (ASD), referred to as autism, is a kind of heterogeneous neurodevelopmental related disease with different etiology, different degree of symptoms and different onset periods.the main clinical symptoms are persistent social communication and language communication barriers, repetitive stereotyped behavior and narrow interest.it is estimated that there is one autistic patient in every 68 children under the age of 8; up to now, the etiology of 75% of autistic patients is still unclear [1].due to the heterogeneity and complexity of clinical manifestations and genetic background of neurodevelopmental diseases represented by autism, it is a difficult problem to clarify the pathogenesis of autism in the field of medicine and life science.Nr2f1 (also known as COUP-TFI) gene is located on chromosome 5.a recent clinical study revealed that Nr2f1 gene mutation was closely related to neurodevelopmental diseases, and about 35% of Nr2f1 gene mutation carriers showed autism symptoms [2].Nr2f1 gene point mutation (grch38. P12; chr5: 93585358 G & gt; a; c.335g & gt; a; p.r112k) is the first patient with autism symptoms and primary Nr2f1 gene point mutation [3].at present, it is not clear how Nr2f1 gene mutation causes neurodevelopmental diseases, especially autism.on April 21, 2020, Tang Ke, School of life sciences, Guangzhou University, Jing Naihe, Center for excellence and innovation in molecular and cell science, Chinese Academy of Sciences, and he Shuijin, School of life science and technology, Shanghai University of science and technology, jointly cooperated in cell The latest research results published online in Reports Magazine: "balance of empirical / occupational neural differentiation in neurodevelopmental disorders with an Nr2f1 point mutation".to solve the above problems, the researchers first used crispr-cas9 gene editing technology to obtain human embryonic stem cells carrying nr2f1-r112k point mutation from autistic patients. Br / > the number of neurons in the ventral part of the brain was significantly inhibited by the number of neurons in the ventral ventral cortex.electrophysiological experiments showed that compared with the normal control neurons, the mutant neurons produced excitatory / inhibitory imbalance (E / I imbalance).sequencing analysis of high-throughput transcriptome (RNA SEQ) and chromatin immunoprecipitation (chip SEQ) showed that the activity of hedgehog signaling pathway was abnormally activated in neural precursor cells on the 20th day of differentiation of mutant embryonic stem cells, and the abnormal neural differentiation of mutant embryonic stem cells could be partially restored by inhibiting hedgehog signaling pathway with cyclopamine.obviously, the abnormal activation of hedgehog signaling pathway caused by nr2f1-r112k point mutation is the cause of imbalance between excitatory neurons and inhibitory neurons.in order to further study the mechanism of action of nr2f1-r112k point mutation in vivo, the researchers constructed the nr2f1-r112k point mutation (Nr2f1 + / M) mouse model.compared with the wild control mice, the number of GAD1 +, PV +, SST + inhibitory intermediate neurons from ventral side of the first sensory cortex in Nr2f1 + / M mutant mice was significantly increased, and the number of cux1 +, CTIP2 + excitatory projection neurons was significantly reduced; meanwhile, the imbalance of cortical electrophysiological excitability and inhibition was also produced.behavioral function analysis showed that Nr2f1 + / M mutant mice exhibited autism related social behavior and repetitive behavior, as well as learning and memory and anxiety behavior related to other neurodevelopmental diseases. ginkgolide A, an inhibitory GABA receptor antagonist, can partially improve the social behavior, repetitive behavior and anxiety behavior of mutant mice. this discovery provides a new molecular basis for the clinical treatment of autism. this work confirmed that the early abnormal development of the dorsal / ventral pattern associated with hedgehog signaling pathway caused excitatory / inhibitory imbalance between cortical projection neurons and intermediate neurons, which may be one of the causes of neurodevelopmental diseases, especially autism. in this study, human embryonic stem cell model in vitro and mouse animal model in vivo were used to provide detailed data and new ideas for exploring the pathogenesis and clinical treatment of autism. this study was jointly completed by Tang Ke, School of life sciences, Guangzhou University; Jing Naihe, Center for excellence and innovation in molecular and Cell Sciences, Chinese Academy of Sciences; and he Shuijin, School of life science and technology, Shanghai University of science and technology. Dr. Zhang Ke, Dr. Yu Fang, Dr. Chen jiehui, experimenter Zhu Jian, Dr. Han su'e and Dr. Wu Xuanyuan are the co first authors of this paper, and Professor Tang Ke, researcher Jing Naihe and Professor He Shuijin are co authors of the paper. the work was carried out by researcher Peng Guangdun, Guangzhou Institute of biomedical and health, Chinese Academy of Sciences / Guangzhou Laboratory of regenerative medicine and health in Guangdong Province, researcher Li Jinsong and Zhao Yun from the center for excellence and innovation in molecular and cell science, Chinese Academy of Sciences, and Chi Chung, University of Toronto Professor Hui and Professor Cheng Leping of Guangxi Medical University strongly supported. original link: references 1, Quesnel Valli è res m, weatheritt RJ, Cordes SP, Blencowe BJ. Autism spectrum disorder: insights into conversion mechanisms from transcriptomics. Nat Rev gene. 2019 Jan; 20 (1): 51-63. Doi: 10.1038/s41576-018-0066-2.2, Chen CA, Bosch DG, CHO MT, Rosenfeld JA, et al. The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype–phenotype correlations. Genet Med. 2016 Nov;18(11):1143-1150. doi: 10.1038/gim.2016.18.3, Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M et al. NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet. 2014 Feb 6;94(2):303-9. doi: 10.1016/j.ajhg.2014.01.002.