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Cited by 59Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchGenetic Neurodegenerative Diseases

Excessive astrocyte-derived neurotrophin-3 contributes to the abnormal neuronal dendritic development in a mouse model of fragile X syndrome.

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Yang, Qi, Feng, Bin, Zhang, Kun, Guo, Yan-yan, Liu, Shui-bing, Wu, Yu-mei, Li, Xiao-qiang, Zhao, Ming-gao·2012·PLoS Genetics
DOI 10.1371/journal.pgen.1003172PMC PMC3531466
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Abstract

Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA-binding motifs and is involved in translational regulation. RNA-binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS.

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  • Secretion of TSP-1 is abnormally reduced from Fmr1 KO astrocytes, whereas NT-3 levels are increased in the secretome of Fmr1 KO astrocytes and in the Fmr1 KO prefrontal cortex compared with controls.

    “Secretion of thrombospondin-1 (TSP-1) that as an extracellular matrix protein may induce cell adherence and induce synaptogenesis is also abnormally reduced from Fmr1 KO astrocytes (Cheng et al., 2016), whereas neurotrophin-3 (NT-3) levels are increased in the secretome of Fmr1 KO astrocytes as well as in the Fmr1 KO prefrontal cortex when compared with controls (Yang et al., 2012).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Yang et al., 2012

    The Results section, “High levels of NT-3 are released from Fmr1 KO astrocytes” (page unavailable), reports higher NT-3 in KO astrocyte-conditioned medium and in the cerebral cortex of young KO mice than in WT controls. It does not identify the cortex sampled for that comparison as prefrontal. The TSP-1 statement is cited to Cheng et al., not to Yang et al. (LLM, conf=0.88)

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Authors
Yang, Q., Feng, B., Zhang, K., Guo, Y.-Y., Liu, S.-B., Wu, Y.-M., Li, X.-Q., & Zhao, M.-G.
Affiliations
Air Force Medical University (CN)
Corresponding author
Zhao, Ming-gao
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2012-12-27
Volume
8
Issue
12
Pages
e1003172
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1003172
PMC
PMC3531466
OpenAlex
W2060647663
Cited by
59
References
54
Citations by year
2026: 3 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 6 · 2016: 10 · 2015: 8 · 2014: 6 · 2013: 4
FWCI
3.47
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (31271144, 2011ZXJ09106‐01C, 31070923)
  • University of Toronto
  • Program for New Century Excellent Talents in University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
fragile X syndrome, neurotrophin-3, astrocytes, FMRP, Fmr1 knockout mice, dendritic development, astrocyte-neuron interaction, prefrontal cortex, CGG repeat expansion, synaptic proteins, RNA-binding proteins, translational regulation, therapeutic target
MeSH terms
Animals, Astrocytes, Cells, Cultured, Dendrites, Disease Models, Animal, Fragile X Syndrome, Nerve Growth Factors, Neurons, Protein Binding, RNA-Binding Proteins, Culture Media, Conditioned, Mice, Knockout, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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