# The Role of Astrocyte BMP Signaling in Fragile X Syndrome

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $53,974

## Abstract

Project Summary/Abstract
This project addresses the role of astrocyte bone morphogenetic protein (BMP) signaling in the pathogenesis of
Fragile X Syndrome (FXS). FXS is the most common inherited form of intellectual disability (ID) and autism
spectrum disorder (ASD). FXS is caused by trinucleotide repeat expansion in the FMR1 gene promoter leading
to transcriptional silencing, and FXS is most often modeled with the Fmr1 knockout (KO) mouse. Although
research has implicated several pathways mediating the effects of the Fmr1 loss of function, most targeted
treatments have failed in clinical trials, and FXS is predominantly treated by symptom only. The majority of
research in FXS has focused on intrinsic changes within neurons. However, emerging research in FXS implicates
astrocytes, specifically through astrocyte-secreted factors. Wild-type (WT) neurons cultured with astrocytes or
astrocyte-conditioned media (ACM) from Fmr1 KO mice exhibit stunted neurite outgrowth and recapitulate the
immature dendritic spine phenotype observed in vivo in Fmr1 KO mice and human FXS patients, providing direct
evidence for a causal role of astrocyte-secreted factors in FXS. Preliminary data profiling FXS astrocyte
transcription and protein secretion identified four proteins both overexpressed in mRNA and oversecreted, one
of which is BMP6. Furthermore, activation of BMP signaling in WT astrocytes generates over a third of the protein
secretion changes of FXS astrocytes, while abrogation of BMP signaling in FXS astrocytes abolishes neurite
outgrowth deficits. The goal of this proposal is to test the hypothesis that BMP signaling in astrocytes is upstream
of neurodevelopmental FXS deficits in vivo and to identify the astrocyte-secreted proteins that mediate this effect.
A combined genetic and viral approach to selective knock out Bmpr2 or Smad4 in astrocytes will be used to
assess whether downregulation of astrocyte BMP signaling can rescue in vivo FXS abnormalities in dendritic
spines, plasticity, and behavior. An astrocyte-specific in vivo proteomic approach combined with characterization
of specific proteins in vitro will identify proteins downstream of BMP signaling responsible for FXS deficits. These
experiments will determine if BMP signaling in astrocytes mediates FXS deficits in vivo and elucidate
mechanisms by which it occurs, thereby providing new insight into a previously underappreciated aspect of FXS
pathophysiology. The proposed research will take place in the Allen Laboratory at the Salk Institute for Biological
Studies, a collaborative research environment that provides access to all necessary equipment and training.
Through theoretical and practical training in molecular neurobiology, collaboration with supporters of diverse
research and clinical backgrounds, and a research team committed to mentorship, the proposed research
training plan will enable rigorous instruction in research and lay the foundation for a future career as an
independent physicia...

## Key facts

- **NIH application ID:** 10909263
- **Project number:** 5F30HD106699-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** James Derong Deng
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909263

## Citation

> US National Institutes of Health, RePORTER application 10909263, The Role of Astrocyte BMP Signaling in Fragile X Syndrome (5F30HD106699-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10909263. Licensed CC0.

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