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Biol. Psychiatry, Oct 18 2025, S0006-3223(25)01534-3 | https://doi.org/10.1016/j.biopsych.2025.10.014
KIAA0319 plays a critical role in cortical neuronal maturation and synaptic development through a dyslexia-associated gene network
Michael J Scandura 1, Mu Seog Choe 1, Ferdi Ridvan Kiral 1, Cynthia Lo 1, Jonghun Kim 1, Woo Sub Yang 1, Caihong Qiu 2, Yinghong Ma 2, Jeffrey R Gruen 3 *, In-Hyun Park 1 *
1Department of Genetics, Yale Stem Cell Center, Interdepartmental Neuroscience Program, Wu Tsai Institute, Yale School of Medicine, New Haven, CT 06520, USA.
2Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
3Departments of Pediatrics and of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
2Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
3Departments of Pediatrics and of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
*Corresponding authors: correspondence to Jeffrey R Gruen or In-Hyun Park
Abstract
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.
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-Cas9 to generate KIAA0319 knockout (KIAA0319 -/-) human embryonic stem cells (hESCs), 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).
To investigate the role of KIAA0319 in neurodevelopment, we used CRISPR-Cas9 to generate KIAA0319 knockout (KIAA0319 -/-) human embryonic stem cells (hESCs), 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 (tRG) 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.
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 (tRG) 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.
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.
논문정보
- Research article
- 2025년 10월 (BRIC 등록일 2025-10-22)
- 국외 연구진
- 생명과학 > 신경생물학
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