# Understanding the Pathogenic Mechanisms of Rett Syndrome

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $519,270

## Abstract

Mutations in methyl-CpG binding protein 2 (MECP2) gene cause Rett Syndrome (RTT), a
neurodevelopmental disorder that afflicts about 1 in 10,000 girls. To understand the pathogenesis of RTT,
we previously developed and characterized mouse models recapitulating RTT-associated missense
mutations, MeCP2 T158M and R106W, and examined MeCP2-dependent gene expression programs in
neuronal cell types of interest. We found that 1) both mutations impair MeCP2 binding to chromatin,
resulting in RTT-like phenotypes in mice, but, elevation of MeCP2 mutant protein expression increase the
binding of MeCP2 to chromatin and ameliorate RTT-like phenotypes in vivo, raising a new direction to
develop therapeutics for RTT; 2) MeCP2 plays a necessary and sufficient role in forebrain GABAergic
interneurons mediating neuronal event-related potentials (ERPs), supporting a key role for MeCP2 to
regulate information processing; and 3) By developing a Cre-dependent biotin tagging system, we
uncovered that MeCP2 modulates gene transcription in a mutation-dependent, cell type-specific, and in
both cell and non-cell autonomous manner, particularly in mosaic females. These findings have set the
premise to uncover the molecular mechanisms by which MeCP2 modulates cell type-specific gene
expression, investigate the molecular etiology of RTT in heterozygous females, and test the causality of
MeCP2-dependent molecular pathways that underlie the pathogenesis of RTT. With the combined
genetic, genomic, molecular and cellular approaches, we hope to not only reveal novel insight into the
pathogenic mechanisms of RTT, but also to expedite the development of mechanism-based therapeutics
to improve treatment for RTT. Moreover, our proposed study will provide the research community at
large with innovative tools and resources to investigate the epigenetic mechanisms underlying a variety of
biological processes and diseases.

## Key facts

- **NIH application ID:** 10242844
- **Project number:** 5R01NS081054-09
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Zhaolan Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $519,270
- **Award type:** 5
- **Project period:** 2013-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242844

## Citation

> US National Institutes of Health, RePORTER application 10242844, Understanding the Pathogenic Mechanisms of Rett Syndrome (5R01NS081054-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242844. Licensed CC0.

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