title: Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.
abstract: Mutations in NIPBL are the most frequent cause of Cornelia de Lange syndrome (CdLS), a developmental disorder encompassing several neurological defects, including intellectual disability and seizures. How NIPBL mutations affect brain development is not understood. Here we identify Nipbl as a functional interaction partner of the neural transcription factor Zfp609 in brain development. Depletion of Zfp609 or Nipbl from cortical neural progenitors in vivo is detrimental to neuronal migration. Zfp609 and Nipbl overlap at genomic binding sites independently of cohesin and regulate genes that control cortical neuron migration. We find that Zfp609 and Nipbl interact with the Integrator complex, which functions in RNA polymerase 2 pause release. Indeed, Zfp609 and Nipbl co-localize at gene promoters containing paused RNA polymerase 2, and Integrator similarly regulates neuronal migration. Our data provide a rationale and mechanistic insights for the role of Nipbl in the neurological defects associated with CdLS.
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK. Electronic address: debbie.vandenberg@crick.ac.uk.
authors.forename: Debbie L C
authors.initials: DLC
authors.lastname: van den Berg
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Azzarelli
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Koji
authors.initials: K
authors.lastname: Oishi
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Martynoga
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Noelia
authors.initials: N
authors.lastname: Urbán
authors.affiliation: Center for Proteomics, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Dick H W
authors.initials: DHW
authors.lastname: Dekkers
authors.affiliation: Center for Proteomics, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Demmers
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK. Electronic address: francois.guillemot@crick.ac.uk.
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003635:De Lange Syndrome / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D012319:RNA Polymerase II; D015534:Trans-Activators; D014157:Transcription Factors; D000097722:Cohesins; C546088:Nipbl protein, mouse; C581924:Zfp609 protein, mouse
keywords: Cornelia de Lange syndrome; Integrator; Nipbl; RNA pol2 pausing; Zfp609; neuronal migration; transcription