Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice

Proceedings of the National Academy of Sciences of the United States of America
Piotr PrzanowskiSanchita Bhatnagar

Abstract

Rett syndrome (RTT) is a genetic disorder resulting from a loss-of-function mutation in one copy of the X-linked gene methyl-CpG-binding protein 2 (MECP2). Typical RTT patients are females and, due to random X chromosome inactivation (XCI), ∼50% of cells express mutant MECP2 and the other ∼50% express wild-type MECP2. Cells expressing mutant MECP2 retain a wild-type copy of MECP2 on the inactive X chromosome (Xi), the reactivation of which represents a potential therapeutic approach for RTT. Previous studies have demonstrated reactivation of Xi-linked MECP2 in cultured cells by biological or pharmacological inhibition of factors that promote XCI (called "XCI factors" or "XCIFs"). Whether XCIF inhibitors in living animals can reactivate Xi-linked MECP2 in cerebral cortical neurons, the cell type most therapeutically relevant to RTT, remains to be determined. Here, we show that pharmacological inhibitors targeting XCIFs in the PI3K/AKT and bone morphogenetic protein signaling pathways reactivate Xi-linked MECP2 in cultured mouse fibroblasts and human induced pluripotent stem cell-derived postmitotic RTT neurons. Notably, reactivation of Xi-linked MECP2 corrects characteristic defects of human RTT neurons including reduced soma si...Continue Reading

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Citations

Sep 26, 2019·Frontiers in Cell and Developmental Biology·Irene TalonVincent Pasque
Sep 30, 2020·Journal of Neurodevelopmental Disorders·Javier Flores GutiérrezEnrico Tongiorgi
Nov 12, 2020·Journal of Neurodevelopmental Disorders·Hyeong-Min LeeAndrea Cerase
Aug 29, 2020·Neuroscience and Biobehavioral Reviews·Sehrish JavedWei-Hsiang Huang
Jan 15, 2021·Pharmaceutical Patent Analyst·Hermann Am Mucke
Apr 15, 2021·Clinical Journal of the American Society of Nephrology : CJASN·Catherine Quinlan, Michelle N Rheault
Aug 14, 2021·Human Molecular Genetics·He FangChristine M Disteche
Nov 26, 2021·Biochemical Society Transactions·Alessandra Spaziano, Dr Irene Cantone

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