Abstract
SummaryMutations 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.
Highlights
The cerebral cortex, responsible for higher cognitive function, is generated from a pool of progenitor cells that will give rise to the neuronal and glial lineages of the adult brain
Zfp609 Is Expressed in Neural Progenitors and Regulates Cortical Neuron Migration Zfp608 and Zfp609 are vertebrate homologs of Drosophila scribbler, a single zinc-finger protein that is highly expressed in the larval CNS, where it is proposed to act as a transcription factor
Zfp608 is expressed in the mouse forebrain subventricular (SVZ) and intermediate zone (IZ) at embryonic day (E)14.5 (Ayoub et al, 2011)
Summary
The cerebral cortex, responsible for higher cognitive function, is generated from a pool of progenitor cells that will give rise to the neuronal and glial lineages of the adult brain. Unperturbed migration of newly born neurons across the expanding cortex to their final destination in specific cortical layers ensures accurate connectivity and neuronal circuit formation. Developmental disturbance of neuronal migration affects shaping of the neuronal network and has been linked to a variety of neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder (ASD), and intellectual disability (Guerrini and Parrini, 2010; Muraki and Tanigaki, 2015; Reiner et al, 2016; Verrotti et al, 2010). Cornelia de Lange syndrome (CdLS) is one particular example of a developmental disorder highlighted by neurological defects, including seizures and intellectual disability. A genetic cause for the remaining 30% of clinically diagnosed CdLS patients remains unknown
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