# Characterization of MeCP2-dependent gene regulation with temporal and mechanistic precision

> **NIH NIH K99** · HARVARD MEDICAL SCHOOL · 2021 · $89,370

## Abstract

PROJECT SUMMARY
Rett syndrome (RTT) is a severe neurodevelopmental disorder that is caused by mutations in the methyl-DNA-
binding protein MeCP2 and represents one of the most common causes of intellectual disability in females. RTT
symptoms include a progressive loss of speech and social engagement, seizures, stereotyped hand movements,
and motor-system disabilities. The monogenic etiology of RTT has enabled the development of MeCP2-mutant
mouse models that display synaptic and behavioral phenotypes that reasonably accurately model RTT
symptoms. Importantly, re-expression of MeCP2 in adult MeCP2-null mice reverses the synaptic and behavioral
phenotypes, suggesting the possibility of ameliorating the cognitive and behavioral difficulties of girls with RTT.
However, the incomplete understanding of MeCP2 molecular function limits therapeutic development. The
proposed study will use new mouse models and approaches to characterize the immediate consequences of
MeCP2 loss and to investigate key neuronal activity-dependent components of MeCP2 function. Aim 1: Of the
many molecular consequences associated with constitutive loss of MeCP2, researchers do not yet know which
are direct results of MeCP2 loss and which are secondary consequences of long-term neurological impairment.
Dr. Boxer will use a new mouse line that enables rapid and specific degradation of the MeCP2 protein to
characterize the molecular, cellular, and behavioral consequences of acute loss of MeCP2 in the brain. These
experiments will reveal the relative order of phenotype appearance, which will enable the identification of the
direct molecular effects of MeCP2 loss and provide insight into the synaptic and behavioral steps of disease
progression. Aim 2: MeCP2 is rapidly phosphorylated at multiple sites in response to neuronal activity, and
MeCP2-null neurons display defects in experience-dependent synaptic refinement. However, the synaptic
refinement phenotype has not been directly or immediately connected to activity-dependent MeCP2
phosphorylation. Dr. Boxer will use a recently developed mouse line with alanine mutations in all activity-
dependent phosphorylation sites to investigate the role of activity-dependent MeCP2 phosphorylation in
regulation of gene expression and synaptic refinement. Overall, these experiments will provide temporally and
mechanistically precise answers to key outstanding questions in MeCP2 research, potentially enabling the
development of targeted therapeutics for RTT. The proposed research will provide training for Dr. Boxer in
electrophysiology and bioinformatics, and more broadly in neurobiology and career development, in the
laboratory of her mentor, Dr. Michael Greenberg, and with guidance from her Advisory Committee at Harvard
Medical School. Dr. Boxer intends to become an academic professor studying the molecular basis of
neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10380926
- **Project number:** 3K99NS112415-02S1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lisa D. Boxer
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $89,370
- **Award type:** 3
- **Project period:** 2021-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380926

## Citation

> US National Institutes of Health, RePORTER application 10380926, Characterization of MeCP2-dependent gene regulation with temporal and mechanistic precision (3K99NS112415-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380926. Licensed CC0.

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