# Towards a Better Understanding of Fragile X Syndrome Using Human Brain Organoids

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $429,000

## Abstract

Project Summary
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic
cause of autism spectrum disorders (ASD). FXS is caused by the loss of functional fragile X mental retardation
protein (FMRP). FMRP, encoded by the FMR1 gene, is a selective RNA-binding protein associated with
translating polyribosomes. Previous works have focused on the role of FMRP as translational regulator and
many mRNA targets of FMRP have been shown to be ASD-linked genes. Epigenetic regulation plays a pivotal
role in neurodevelopment and neuropsychiatric disorders, including ASD. In addition to DNA and histone
modifications, more than 150 post-transcriptionally modified ribonucleosides have been identified in various
types of RNA. Among different RNA modifications, N6-methyladenosine (m6A) is by far the best-known
modification on mRNA and lncRNA. m6A is dynamically regulated with dedicated writer, eraser, and reader
proteins. m6A significantly affects RNA splicing, export, localization, translation efficiency and stability. We
have found that the temporal and spatial distribution of m6A during neurodevelopment is highly dynamic, and
the m6A-marked transcripts are enriched among ASD-linked genes as well as the mRNA targets of fragile X
mental retardation protein (FMRP). Our biochemical analyses as well as the work of others have found that
FMRP could bind to the m6A sites of its mRNA targets (m6A reader). Furthermore, we found that FMRP could
maintain the stability of its mRNA targets, suggesting a new biological role of FMRP in gene regulation.
Human-induced pluripotent stem cells (iPSCs) are pluripotent and are able to generate many different cell
types. Three-dimensional (3D) aggregate culture of iPSCs has evolved from embryoid body culture, quite
faithfully following human organogenesis, and provides a new platform to investigate human brain
development in a dish, otherwise inaccessible to experimentation. Our preliminary data suggest that the loss of
FMRP could alter the development of human forebrain organoids. Furthermore, recently published data
suggest that m6A modification is more pervasive during neurodevelopment in human than mouse. In this
proposed study, we will develop and characterize the human forebrain organoids of FXS and identify the
potential human-specific mRNA targets of FMRP during human brain development. Our proposed works will
lead to the development of the human forebrain organoid model for FXS and potentially identify the human-
specific FMRP targets.

## Key facts

- **NIH application ID:** 10038026
- **Project number:** 1R21MH123711-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Zhexing Wen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2020-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10038026

## Citation

> US National Institutes of Health, RePORTER application 10038026, Towards a Better Understanding of Fragile X Syndrome Using Human Brain Organoids (1R21MH123711-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10038026. Licensed CC0.

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