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<p>Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the <i>FMR1</i> gene leading to the loss of FMRP, an RNA-binding protein that regulates local mRNA translation in neuronal dendrites, crucial for synapse development. Three-dimensional (3D) brain organoid models derived through in vitro differentiation of pluripotent stem cells offer a powerful tool to dissect the underlying mechanisms of neurodevelopmental disorders. Here, we generated human FXS and control organoids using isogenic human embryonic stem cell clones with and without the FXS mutation. Our results show that mature FXS cortical brain organoids can be derived by inhibiting the TGFβ and Wnt pathways. Moreover, expression analyses including immunofluorescence, qRT-PCR, proteomics and western blotting reveal altered levels of neuronal markers and ECM deposition along with modulated downstream signaling molecules. Interestingly, in silico analysis of proteomics revealed several altered pathways, such as cell adhesion, regulation of neurogenesis and cell cycle that are implicated in FXS. Collectively, our unique FXS-organoids derived from isogenic hESC lines may serve as a model for studying the pathology of FXS disorder and for developing therapeutical intervention.</p>

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Altered ECM deposition and cell adhesion signaling in a human cortical organoid model of fragile X syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Sapir Havusha-Laufer,
  • Venkat Raghavan Krishnaswamy,
  • Noy Krugliak-Shechter,
  • Anjana Shenoy,
  • Maayan Karlinski Zur,
  • Liron Kuznitsov-Yanovsky,
  • Inna Solomonov,
  • Jacob H. Hanna,
  • Irit Sagi,
  • Dalit Ben Yosef

摘要

Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the FMR1 gene leading to the loss of FMRP, an RNA-binding protein that regulates local mRNA translation in neuronal dendrites, crucial for synapse development. Three-dimensional (3D) brain organoid models derived through in vitro differentiation of pluripotent stem cells offer a powerful tool to dissect the underlying mechanisms of neurodevelopmental disorders. Here, we generated human FXS and control organoids using isogenic human embryonic stem cell clones with and without the FXS mutation. Our results show that mature FXS cortical brain organoids can be derived by inhibiting the TGFβ and Wnt pathways. Moreover, expression analyses including immunofluorescence, qRT-PCR, proteomics and western blotting reveal altered levels of neuronal markers and ECM deposition along with modulated downstream signaling molecules. Interestingly, in silico analysis of proteomics revealed several altered pathways, such as cell adhesion, regulation of neurogenesis and cell cycle that are implicated in FXS. Collectively, our unique FXS-organoids derived from isogenic hESC lines may serve as a model for studying the pathology of FXS disorder and for developing therapeutical intervention.