The Function And Mechanism Of Menin In The Nervous System

Early developmental defect of the nervous system caused by abnormal gene expression results in many neurological diseases(including autism,schizophrenia,etc.).Functional research on MEN1(Multiple endocrine neoplasia I)has been mainly focused on the field of cancer and its role in the nervous system has been overlooked.Abnormal expression of menin can cause a familial genetic disease of malignant tumors in multiple endocrine glands.Menin,encoded by MEN1,mainly acts as a transcription factor and participates in regulating the transcription of downstream genes.The mouse model of systemic Men1 knockout is embryonic lethal,accompanied by severe neural tube defects.Our previous studies found that menin expresses highly abundantly in multiple brain regions,especially in the hippocampus,indicating that menin plays an important role in the nervous system.Therefore,we used Cre-LoxP system to construct a mouse model that specifically knocked out Men1 in various types of cells in the nervous system.We found that the excitatory neuron specific knockout Men1 mice showed a series of behavioral defects.In the first part of the work,we demonstrated that menin can affect the kinase activity of Cdk5 by regulating the expression of CDK5 regulator p35;Menin deficiency reduced p35 protein level and consequently the loss of Cdk5 kinase activity,which in turn leads to a decrease in synaptic plasticity and cognitive deficits in mice.Expression of human p35 by AAV transduction can alleviate cognitive deficits in Men1-deficient mice.In the second part of our work,we conducted more comprehensive behavioral analyses of excitatory neuron-specific Men1-deficient mice and found that in addition to cognitive deficits,the mice exhibited social disorders and increased repetitive behavior.Using a combination of ChIP-Seq and RNA-Seq,we discovered that menin can bind to the promoter of FoxGl(an important gene that has been linked to Rett syndrome)and upregulation(or downregulation)its expression.In addition,we also used IP(Immunoprecipitation)and LC-MS(liquid chromatography-tandem mass spectrometry)to identify the potential interacting factors for menin;ATRX and TOP2β were identified.The relationship between the two and neurodevelopmental diseases(such as autism et.al.)has been previously reported.Whether these potential factors can participate in the regulation of FoxG1 expression together with menin remains unknown and warrants further scrutiny.Taken together,our study demonstrate that the loss of menin suppresses p35 expression and Cdk5 activity,and results in cognitive impairment in rodents.Menin interacts with specific transcription factors(ATRX or TOP2β)to regulate the expression of FoxG1,resulting in phenotypes recapitulating Rett syndrome,which may represent a new mechanism underlying Rett syndrome.