The Abnormal Lateral Ventricle Niche Caused By The Absence Of TET1 Led To Hydrocephalus

Objective:To reveal the phenotype of hydrocephalus in TET1 knockout mice(TET1 KO)and further explore the physiological phenomenon and molecular mechanism that may induce hydrocephalus.Materials and methods:Morphological changes were detected by computed tomography(CT),nuclear magnetic resonance water imaging(MRH),HE staining and Nissl staining.Immunofluorescence staining was used to detect the appearance of ependymal cell layer and the cilia of lateral ventricle in TET1 knockout mice Transcriptome sequencing data of TET1 KO mice brain tissue samples were analyzed to reveal the underlying molecular mechanisms.Results:TET1 KO mice were successfully bred and knockout mice of different ages were selected for the study.Water content of brain tissues of mice was detected by computed tomography(CT)and Magnetic Resonance Hydrography(MRH),confirming that TET1 KO mice had more severe hydrocephalus than wildtype(WT).HE staining showed that the lateral ventricle of TET1 KO mice was significantly larger than that of WT mice,and there was no abnormal development of aqueduct and venation.By Nissl staining,it was found that TET1 KO mice showed significant cortical thinning compared with WT mice.Immunofluorescence staining confirmed that S100?,GFAP,BLBP in ependymal cell layer of TET1 KO mice were significantly reduced,which Suggested that ependymal cells,astrocytes,and radial oligodendrocytes on ependymal of TET1 KO mice were significantly reduced.Using immunohistochemistry to further observed the decrease of cilia in the ependymal layer of TET1 KO mice.In addition,through RNA transcriptome sequencing and bioinformatics analysis,TET1 KO mice showed significant changes in brain tissue compared with WT mice,in which the expression of 93 genes increased and the expression of 150 genes decreased.The cluster analysis of biological functions revealed that the genes with abnormal expression were most channel-related proteins.By quantitative PCR,it was found that the deficiency of TET1 impaired the transcription processes of some proteins including channel related proteins such as AQP3 and SLC17A7,inflammatory related factors such as CXCL10,glial cell differentiation related genes such as PLP1,and AP1S2,which have been reported to cause hydrocephalus.Conclusion:TET1 knockout mice had severe hydrocephalus with obvious ventricular enlargement and cortical thinning.The loss of TET1 leads to the damage of ependymal cells in the lateral ventricle,and the decrease of astrocytes and radial glial cells.At the same time,abnormal expression of some protein transcription levels appeared,including AQP3,GAL10,CXCL10,PLP1,and AP1S2.