The study utilized human forebrain organoids derived from induced pluripotent stem cells (iPSCs) of Williams Syndrome (WS) patients to investigate the underlying mechanisms of the neuronal deficits associated with this disorder. The key findings are:
Neural progenitor cells (NPCs) in WS forebrain organoids displayed abnormal proliferation and differentiation capabilities, as well as impaired synapse formation. Bulk RNA-seq analysis revealed altered expression of genes related to neuronal development and neurogenesis.
Single-cell RNA-seq (scRNA-seq) data analysis showed an aberrant generation of excitatory neurons in WS organoids, with a decreased proportion of deep layer and upper layer projection neurons.
Mechanistically, the expression of transthyretin (TTR) was significantly decreased in WS forebrain organoids. The transcription factor GTF2IRD1, encoded by one of the WS-associated genes, binds to the TTR promoter and regulates its expression.
Exogenous TTR could activate the ERK signaling pathway and rescue the neurogenic deficits of WS forebrain organoids. Gtf2ird1-deficient mice also displayed similar neurodevelopmental deficits as observed in the WS organoids.
Collectively, the study reveals a critical function of the GTF2IRD1-TTR-ERK axis in regulating neurodevelopment and provides novel insights into the mechanisms underlying the abnormal neurogenesis in Williams Syndrome.
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biorxiv.org
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by Zhao,X., Sun... ב- www.biorxiv.org 04-25-2024
https://www.biorxiv.org/content/10.1101/2024.04.25.591131v1שאלות מעמיקות