Impact of MeCP2 Overexpression on Myelination Defects Found in Pitt-Hopkins Syndrome Model Mice. Journal Article

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Authors: Freitas, GA; Vermudez, SAD; Gogliotti, RG; Niswender, CM
Article Title: Impact of MeCP2 Overexpression on Myelination Defects Found in Pitt-Hopkins Syndrome Model Mice.
Abstract: INTRODUCTION: Studies examining neurodevelopmental disorders (NDDs) have emphasized a relationship between Pitt Hopkins syndrome (PTHS), which is caused by mutations in the Transcription Factor 4(TCF4) gene, and myelination defects that suggest novel molecular phenotypes in NDDs (Phan et al., 2020). Known phenotypic overlap between PTHS and Rett syndrome (RTT) suggests that there are possible common signaling pathways between the two NDDs. We have found that increasing expression of Methyl-CpG-Binding Protein 2 (MeCP2), the causative protein in most cases of RTT, decreases hyperactivity and corrects impairments in learning and memory in a mouse model of PTHS (Tcf4 ). AIM: The current study sought to understand if the positive effects of MeCP2 overexpression on behavioral phenotypes in the Tcf4 model were due to a reversal of myelination deficits. METHODS/RESULTS: We generated four distinct animal genotypes (WT, MECP2 , Tcf4 , MECP2 ; Tcf4 ) and performed RNA-sequencing from the hippocampus and striatum followed by quantitative RT-PCR, revealing that myelin-associated genes are differentially expressed in MECP2 ; Tcf4 mice in both brain regions. However, Western blotting revealed decreased expression for the myelinating oligodendrocytes (OLs) protein Myelin Oligodendrocyte Glycoprotein (MOG) in mice of both the Tcf4 and MECP2 ; Tcf4 genotypes without changes in the OL precursor cell marker Chondroitin Sulfate Proteoglycan (NG2). We are currently quantifying potential changes in OL morphology and number (mature and immature cells), and myelin synthesis via immunohistochemistry of brain sections. CONCLUSIONS: Altogether, our preliminary results indicate that behavioral phenotypic rescue in MECP2 ; Tcf4 mice may not result from a correction of myelination deficits characteristic of Tcf4 animals.
Journal Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860; 0892-6638
Publisher: Unknown  
Date Published: 2022