Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration

Neuron. 2017 Jan 18;93(2):348-361. doi: 10.1016/j.neuron.2016.11.047. Epub 2016 Dec 29.


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.

Keywords: Cornelia de Lange syndrome; Integrator; Nipbl; RNA pol2 pausing; Zfp609; neuronal migration; transcription.

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Movement / genetics*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • De Lange Syndrome / genetics*
  • Gene Expression Regulation, Developmental*
  • Mice
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Neurons / cytology*
  • Neurons / metabolism
  • Promoter Regions, Genetic
  • RNA Polymerase II / metabolism
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Nipbl protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Zfp609 protein, mouse
  • cohesins
  • RNA Polymerase II