TY - JOUR
T1 - The X-Linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain
AU - Zhang, Chi
AU - Mejia, Luis A.
AU - Huang, Ju
AU - Valnegri, Pamela
AU - Bennett, Eric J.
AU - Anckar, Julius
AU - Jahani-Asl, Arezu
AU - Gallardo, Gilbert
AU - Ikeuchi, Yoshiho
AU - Yamada, Tomoko
AU - Rudnicki, Michael
AU - Harper, J. Wade
AU - Bonni, Azad
N1 - Funding Information:
We thank the members of the Bonni laboratory for helpful discussions and critical reading of the manuscript. This work was supported by NIH grants NS041021 (A.B.), GM054137 (J.W.H), and AG011085 (J.W.H).
PY - 2013/6/19
Y1 - 2013/6/19
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84879251172&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2013.04.021
DO - 10.1016/j.neuron.2013.04.021
M3 - Article
C2 - 23791194
AN - SCOPUS:84879251172
SN - 0896-6273
VL - 78
SP - 986
EP - 993
JO - Neuron
JF - Neuron
IS - 6
ER -