title: The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain.
abstract: Intellectual disability is a prevalent disorder that remains incurable. Mutations of the X-linked protein PHF6 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 in vivo, 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 in vivo. 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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Luis A
authors.initials: LA
authors.lastname: Mejia
authors.forename: Ju
authors.initials: J
authors.lastname: Huang
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bennett
authors.forename: Julius
authors.initials: J
authors.lastname: Anckar
authors.forename: Arezu
authors.initials: A
authors.lastname: Jahani-Asl
authors.forename: Gilbert
authors.initials: G
authors.lastname: Gallardo
authors.forename: Yoshiho
authors.initials: Y
authors.lastname: Ikeuchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada
authors.forename: Michael
authors.initials: M
authors.lastname: Rudnicki
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D050172:Genes, X-Linked / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics*; D051379:Mice; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D012097:Repressor Proteins
chemical_list: D002352:Carrier Proteins; D018398:Homeodomain Proteins; C526788:Phf6 protein, mouse; C547921:RNA polymerase II associated factor 1, mouse; D012097:Repressor Proteins