# Early developmental mechanisms of Rett Syndrome

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $385,688

## Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting girls. In its classical form, RTT
is predominantly caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). MeCP2 is
a multifunctional regulator of gene expression which regulates transcription through diverse mechanisms such
as DNA-binding, interaction with transcription factor complexes, modulation of chromatin structure and regulation
of miRNAs – mechanisms that are engaged pleiotropically through different developmental stages. MeCP2 was
considered to act predominantly through late development into adulthood, but recent clinical studies of RTT
children point to very early signs of the disorder. The early developmental mechanisms of MeCP2 are poorly
understood. We previously used RTT patient iPSCs to show that reduction of MeCP2 leads to overexpression
of miRNA-199 and miRNA-214, an increase in neural progenitors, and reduction in neurogenesis and neuronal
migration in cortical organoids. We now propose to analyze the migration deficits in detail, and examine the
mechanisms underlying the deficits. The objective of this proposal is to develop a novel live-cell imaging platform
merging 3D stem cell technologies, microfluidics and multiphoton microscopy, and combine it with state-of-the-
art molecular approaches, including mass spectrometry proteomics and single cell RNA sequencing, to examine
mechanisms of neuronal migration deficits associated with RTT-causing mutations in MECP2. In Aim 1, we
propose to develop label-free third-harmonic generation three-photon microscopy and use it to characterize
neuronal migration deficits in RTT organoids compared to isogenic controls. We will additionally develop a
microfluidics-based live imaging platform where organoids can be stably imaged and neurons tracked for days.
In Aim 2, we will examine the consequence of MECP2 mutations on downstream molecular pathways involved
in neuronal differentiation and migration. We will examine mechanisms of anomalous overexpression of AKT in
RTT organoids and neural progenitors, and use a proteomic and phospho-proteomic screen to define new
proteins and pathways of neuronal migration dysregulated in RTT. We will exploit the transcriptomic profile of
single cells to reveal cell types, populations and transcriptomic differences between RTT and control organoids.
In Aim 3, we will use the technologies of Aim 1, and results of Aim 2, to examine the role of implicated signaling
pathways in neuronal migration. We will interrogate the function of AKT and downstream signaling molecules,
and that of new proteins, including modulators of cell adhesion and cytoskeleton organization identified from our
screens, that are predicted as involved in migration. We will validate in vivo in mice the ability of specific pathways
and focal adhesion proteins to rescue RTT neuronal migration deficits. Together, we expect that these results
will advance our understanding of mechanisms involved...

## Key facts

- **NIH application ID:** 10218706
- **Project number:** 2R01MH085802-11A1
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** MRIGANKA SUR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,688
- **Award type:** 2
- **Project period:** 2009-12-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218706

## Citation

> US National Institutes of Health, RePORTER application 10218706, Early developmental mechanisms of Rett Syndrome (2R01MH085802-11A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218706. Licensed CC0.

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