# Interrogate FMRP functions in primate brain development

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $709,654

## Abstract

Fragile X Syndrome (FXS), caused by deficiency of RNA binding protein Fragile X Messenger
Ribonucleoprotein 1 protein (FMRP), encoded by X-linked FMR1 gene, is the most common
heritable cause of intellectual disability and a top contributor to autism spectrum disorders (ASD).
The mechanisms underlying FXS are not fully clear. Our knowledge of FMRP functions in the
mammalian brain are mostly obtained from rodent studies. However, there are significant
differences between primate and rodent brains, particularly in the prefrontal cortex (PFC) where
FMRP is highly expressed. PFC is critical for myriad higher-order brain functions, such as working
memory, planning, decision-making, language, and creative intelligence, which are severely
affected in FXS. Primate PFC is significantly larger proportionally and much more complex
compared to other species and exhibit gene signatures unique to primates. To date, clinical trials
based on rodent models have not achieved primary endpoints highlighting a critical need for
complementary primate models to better understand FXS. FMRP binds many mRNAs in the brain.
An established role of FMRP is that it promotes neuronal maturation and synaptogenesis during
postnatal development,. On the other hand, FMRP is also robustly expressed in human and
mouse cortex during prenatal development and its deficiency affects mouse cortical development.
In contrast to its well-established role in postnatal brain development and function, the role of
FMRP in prenatal brain development is not well studied, especially in primates. In addition,
Developmental stage-specific roles of FMRP have not been fully investigated and primate-specific
targets of FMRP have not been systematically identified. The goal of this project is to investigate
functions of FMRP in primate prenatal brain development and unveil developmental stage-specific
roles of FMRP in primate brains. We will test the hypothesis that FMRP regulates genes critical
for functional maturation of PFC neurons, and its deficiency leads to altered gene expression and
impaired cortical development. We determine the impact of FMRP-deficiency on gene expression
changes that impair neuronal maturation during primate prenatal development using Patch-seq.
We will identify FMRP-mRNAs and FMRP-protein interactomes in the PFC that regulate primate
brain development using CLIP-seq and Co-IP-mass spectrometry, respectively. The proposed
work will fill a major gap of our knowledge in understanding function of FMRP in primate brain
development. Such understanding is critical for better therapeutic development for FXS as well
as other neurodevelopmental disorders including ASD.

## Key facts

- **NIH application ID:** 10858890
- **Project number:** 1R01MH136152-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Xinyu Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $709,654
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10858890

## Citation

> US National Institutes of Health, RePORTER application 10858890, Interrogate FMRP functions in primate brain development (1R01MH136152-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10858890. Licensed CC0.

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