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. NIPBL mutations cause Cornelia de Lange syndrome, but Nipbl function in brain development is not well understood. Van den Berg et al. show that Nipbl interacts with Zfp609 and the Integrator complex to transcriptionally regulate cortical neuron migration.

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Keywords Cornelia de Lange syndrome, Integrator, Neuronal migration, Nipbl, RNA pol2 pausing, Transcription, Zfp609
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Journal Neuron
van den Berg, D.L.C, Azzarelli, R. (Roberta), Oishi, K. (Koji), Martynoga, B. (Ben), Urbán, N. (Noelia), Dekkers, D.H, … Guillemot, F. (2017). Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration. Neuron, 93(2), 348–361. doi:10.1016/j.neuron.2016.11.047