Title: Fragile X Autosomal Homolog 1 (FXR1) is Required for the Development of Human Dorsal Forebrain Excitatory Neurons
Abstract: Fragile X autosomal homolog 1 (FXR1) is a brain-enriched RNA-binding protein essential for neurodevelopment, as its loss of function is intolerant in humans and neonatal lethal in mice. Despite the importance of FXR1, its function in human neurons remains poorly understood. Using human induced pluripotent stem cells (iPSCs), we discovered that FXR1 deficiency leads to decreased proliferation of neural progenitors (NPCs) and impaired differentiation into dorsal forebrain excitatory neurons (exNs). In addition, FXR1 deficient human neurons have impaired morphogenesis and electrophysiological activity. Transcriptomics analysis revealed that FXR1-deficient NPCs and neurons have dysregulated genes and pathways important for neuronal differentiation, synaptic maturation, and neuronal activity. These findings suggest that FXR1 is a critical regulator from the progenitor stage to neuronal maturation, providing new insight into the regulation of human neurogenesis by RNA binding proteins.
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