Biological psychiatry · 2025
KIAA0319 Plays a Critical Role in Cortical Neuronal Maturation and Synaptic Development Through a Dyslexia-Associated Gene Network.
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Scandura Michael J, Choe Mu Seog, Kiral Ferdi Ridvan, Lo Cynthia, Kim Jonghun, Yang Woo Sub, Qiu Caihong, Ma Yinghong, Gruen Jeffrey R, Park In-Hyun
Аннотация
BACKGROUND: Dyslexia is a common learning disorder characterized by difficulty processing written language despite normal intelligence and adequate educational resources. KIAA0319 is one of nine genes reproducibly associated with reading performance, but the molecular basis of its function remains unclear.
METHODS: To investigate the role of KIAA0319 in neurodevelopment, we used CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 to generate KIAA0319 knockout (KIAA0319-/-) human embryonic stem cells, which were then differentiated into human cortical organoids (hCOs). We assessed developmental and transcriptomic changes using morphological analysis, immunostaining, EdU assays, calcium imaging, and single-cell RNA sequencing (scRNA-seq).
RESULTS: KIAA0319-/- hCOs were smaller, displayed morphological abnormalities, and showed disrupted neurogenesis and impaired neuronal maturation. scRNA-seq showed that KIAA0319-/- neural progenitor cells favored a truncated radial glia fate over neuronal maturation. Transcriptomic analysis showed coordinated dysregulation across multiple dyslexia-associated genes, implicating KIAA0319 in a broader regulatory network involved in primary cilia formation, cortical organization, and neural network connectivity.
CONCLUSIONS: These findings suggest that dyslexia-associated genes, including KIAA0319, may regulate core neurodevelopmental processes beyond reading and language, pointing to a broader biological framework for understanding the etiology of dyslexia.
METHODS: To investigate the role of KIAA0319 in neurodevelopment, we used CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 to generate KIAA0319 knockout (KIAA0319-/-) human embryonic stem cells, which were then differentiated into human cortical organoids (hCOs). We assessed developmental and transcriptomic changes using morphological analysis, immunostaining, EdU assays, calcium imaging, and single-cell RNA sequencing (scRNA-seq).
RESULTS: KIAA0319-/- hCOs were smaller, displayed morphological abnormalities, and showed disrupted neurogenesis and impaired neuronal maturation. scRNA-seq showed that KIAA0319-/- neural progenitor cells favored a truncated radial glia fate over neuronal maturation. Transcriptomic analysis showed coordinated dysregulation across multiple dyslexia-associated genes, implicating KIAA0319 in a broader regulatory network involved in primary cilia formation, cortical organization, and neural network connectivity.
CONCLUSIONS: These findings suggest that dyslexia-associated genes, including KIAA0319, may regulate core neurodevelopmental processes beyond reading and language, pointing to a broader biological framework for understanding the etiology of dyslexia.