Med13l Deficiency In Cortical Excitatory Neurons Impairs Neurogenesis And Motor Behaviors In Mice

The MED13 L gene locates in the 12q24.21 region of the human chromosome and its transcript is approximately 319 kb long,containing 31 exons encoding 2210-2203 amino acids.The MED13 L protein encoded by this gene is an important component of the Mediator complex.It is involved in the Cyclin-dependent kinase 8(CDK8)module,regulating the binding and dissociation of the CDK8 module to and from the main body of the Mediator complex.When the two associate,they block RNA polymerase-II(PolⅡ)recruitment and the assembly of transcription initiation complexes,thereby inhibiting gene transcription.MED13 L has been found to be one of the most vulnerable pathogenic genes and diseases resulting from its haploinsufficiency or mutation are collectively referred to as MED13 L syndrome.Most patients with MED13 L syndrome have intellectual disability(ID),speech delay,delayed motor development,physical dysmorphism and distinctive facial features,with about 19% having autism spectrum disorder(ASD),and a small proportion having associated congenital heart defects,immune deficiency,and a thin corpus callosum.Although the clinical phenotype of MED13 L syndrome has been well described,there are few reports on its pathogenic mechanisms and effective treatment methods.In addition,a suitable animal model for this disease remains lacking.Previously,our laboratory constructed MED13 L knockoff mice(Med13L-KO)and studied their phenotypes.We have found that Med13L-KO mice is microcephaly similar to the phenotype of MED13 L syndrome patients,which was associated with abnormalities in cortical neuronal genesis.Adult Med13l-KO mice were also found to have abnormalities in anxiety levels,learning and memory,motor balance,as well as motor coordination.Based on these previous results,the present study investigated the function of Med13 l in the cortical excitatory neuronal lineage and the impact of its deficiency on brain morphology and animal behavior using a Cre-lox P gene conditional knockout strategy.We successfully constructed a floxed allele of Med13 l to specifically ablate this gene in excitatory neurons of the forebrain by crossing the floxed allele with Emx1-cre(Med13l-c KO).We found Med13l-c KO mice had significant thinning of the motor cortex and the corpus callosum,abnormalities in the laminar structure of the cortex,the number of intermediate progenitors and deep layer neurons decreased at the early stage of neurogenesis,reduced total length,number and complexity of dendritic branching of deep layer neurons in adult.Adult Med13l-c KO mice also displayed impaired motor balance and motor coordination,whereas their spatial learning memory and anxiety levels seemed to be largely normal.These findings illustrate that Med13 l regulates the neurogenesis of cortical excitatory neurons during embryonic development and is essential for neuronal morphogenesis and for animal motor behavior.