| Abstract |
Intellectual disability is a prevalent disorder that remains incurable. Mutations of the X-linked protein�PHF6cause the intellectual disability disorder B�rjeson-Forssman-Lehmann syndrome (BFLS). However, the biological role ofPHF6relevant to BFLS pathogenesis has remained unknown. We report that knockdown ofPHF6profoundly impairs neuronal migration in the mouse cerebral cortex in�vivo, leading to the formation of white matter heterotopias displaying neuronal hyperexcitability. We find thatPHF6physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies thePHF6knockdown-induced migration phenotype in�vivo. We also identify Neuroglycan C/Chondroitin sulfate proteoglycan 5 (NGC/CSPG5), a potential精神分裂症susceptibility gene, as a critical downstream target ofPHF6in the control of neuronal migration. These findings definePHF6, PAF1, and NGC/CSPG5 as components of a cell-intrinsic transcriptional pathway that orchestrates neuronal migration in the brain, with important implications for the pathogenesis of developmental disorders of cognition. |