Role And Mechanism Of Autism Risk Gene Tbr1 In Forebrain Axon Projection

Autism spectrum disorders(ASDs)are neurodevelopmental disorders characterized by social disorders and repetitive stereotyped behaviors.At present,there are no drugs and methods to treat the core symptoms of autism,and the fundamental reason is that people’s understanding of the pathogenic mechanism of autism is still in its infancy.The ASD high-risk gene Tbr1 is specifically highly expressed in the forebrain in early development,and its mutation leads to abnormal axon projection of the forebrain in mice,supporting the brain connection hypothesis,but its mechanism regulating axonal orientation is not yet understood.Our previous research found that the zebrafish tbr1 gene is also specifically expressed in the forebrain,and its mutation leads to autismlike behavior,and there are also abnormal forebrain connections.In this study,we further explored the mechanism of action of tbr1 in forebrain neural projection.We found that tbr1 deficiency not only leads to a decrease in anterior joint projections,but also leads to an abnormal increase in axonal tracts in the supraoptic tract(SOT)tract connecting the telencephalon and the thalamus,and these abnormal projections of the forebrain may be an important cause of abnormal behavior.Zebrafish forebrain development is evolutionarily highly conserved with mammals.The Tbr1-Fezf2 molecular network regulates cortical neuron fate in mammals.Zebrafish SOT corresponds to cortical thalamic tract,and tbr1 mutation also leads to abnormal upregulation of its target gene fezf2,and the expression of its downstream gene ctip2(bcl11b)is also increased,which may be an important reason for the abnormal increase in SOT.We found that the tbr1 mutation led to an increase in the expression of L-type voltage-gated calcium channels,as well as an increase in its downstream effector kinase Cam KIV.At the same time,axon-guiding factors that regulate forebrain projection,such as slit-robo2 and netrin-neo1,are abnormally expressed.These results suggest that these molecular networks appear to regulate early axonal projections in a cascade between the fate determinants fezf2 and axon guidance factors in zebrafish,with L-type calcium channels acting as "relay stations".Several members of this molecular network,such as FEZF2,CTIP2 and L-type calcium channels(CAV1.2 and CAV1.3),are also autism risk genes themselves,suggesting that this molecular network regulated by TBR1 may represent a common mechanism for autism pathogenesis.In summary,in this project,we explore the role and mechanism of autism risk gene tbr1 in zebrafish forebrain axon projection.represented by zebrafish AC/SOT,reveal the potential common mechanism of tbr1 regulation of forebrain junction,provide strong evidence for tbr1 to support the brain connection hypothesis,and provide a research model and potential prevention and treatment target for in-depth exploration of the pathogenic mechanism of autism.