The X-Linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain

Chi Zhang, Luis A. Mejia, Ju Huang, Pamela Valnegri, Eric J. Bennett, Julius Anckar, Arezu Jahani-Asl, Gilbert Gallardo, Yoshiho Ikeuchi, Tomoko Yamada, Michael Rudnicki, J. Wade Harper, Azad Bonni*

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Intellectual disability is a prevalent disorder that remains incurable. Mutations of the X-linked proteinPHF6 cause the intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). However, the biological role of PHF6 relevant to BFLS pathogenesis has remained unknown. We report that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex invivo, leading to the formation of white matter heterotopias displaying neuronal hyperexcitability. We find that PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype invivo. We also identify Neuroglycan C/Chondroitin sulfate proteoglycan 5 (. NGC/CSPG5), a potential schizophrenia susceptibility gene, as a critical downstream target of PHF6 in the control of neuronal migration. These findings define PHF6, 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

Original languageEnglish (US)
Pages (from-to)986-993
Number of pages8
JournalNeuron
Volume78
Issue number6
DOIs
StatePublished - Jun 19 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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