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Transcriptomic analysis of human Fragile X syndrome neurons reveals neurite growth modulation by the TGFβ/BMP pathway

ABSTRACT: Isogenic hESC clones with and without the FX mutation that share the same genetic background were in vitro differentiated into neurons. FX neurons present delayed neuronal development and maturation with full FMRP silencing. Following enrichment of neurons in the culture by MACS, transcriptome analysis by RNA sequencing at different time points during differentiation demonstrated dysregulation of the TGFβ/BMP signaling pathway and genes related to the extracellular matrix. FX neurons showed decreased neurite outgrowth that was rescued by inhibition of the TGFβ/BMP signaling pathway, this treatment did not affect the outgrowth of control neurons. In FMRP expressing neurons the regulation of the TGFβ/BMP pathway allow typical neurite outgrowth and axonogenesis that will eventually result in normal neuronal network activity. In contrast, in FX neurons the lack of FMRP dysregulate members of the BMP signaling pathway associated with the ECM organization that in a yet unknown mechanism, reduces the guidance of axonal growth cones, leading to an aberrant neuronal network function. Overall, our results provide new insights into the molecular pathways by which loss of FMRP affects neuronal network development which probably leads to its aberrant function in FXS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206088 | GEO | 2022/08/31

REPOSITORIES: GEO

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Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.

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Transcriptomic analysis of human Fragile X syndrome neurons reveals neurite growth modulation by the TGFβ/BMP pathway

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