BAZ1B haploinsufficiency and the neurophenotypes of Williams syndrome

  • Awarded: 2015
  • Award Type: Explorer
  • Award #: 380465

Williams syndrome (WS) is a neurodevelopmental disorder caused by deletions in the 7q11.23 chromosomal region. Individuals with WS show developmental delays, learning disabilities and excessively social behavior. Interestingly, individuals with duplications of this same chromosomal region display a symmetrically opposite phenotype with regard to social behavior. This genomic segment therefore offers a unique opportunity to understand the molecular underpinnings of social behaviors.

Kenneth S. Kosik and his team at the University of California, Santa Barbara have recently assessed the transcriptomes of induced pluripotent stem cell (iPSC)-derived neurons obtained from individuals with WS and from healthy controls. Haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B explained nearly half of the brain-related transcriptomic dysregulation. The resulting downstream effects of this deletion, and other gene dysregulation, leads to a selective acceleration of neuronal maturation.

Kosik and his team aim to further assess the molecular pathway(s) underlying the phenotypes associated with alterations in 7q11.23 copy number. Based on differential gene expression in iPSC-derived neurons from WS individuals (as assessed by RNA sequencing [RNAseq]), as well as BAZ1B chromatin immunoprecipitation (ChIP) assays with sequencing (CHIPseq) and BAZ1B knock down, the team hypothesizes that the BAZ1B haploinsufficiency in the WS microdeletion results in premature cell cycle exit of neural precursor subsets and an acceleration in neuronal maturation. BAZ1B target genes are enriched for Wnt signaling genes, and this pathway is activated in WS neurons. Wnt signaling regulates the balance between neuronal progenitor proliferation and differentiation, with loss-of-function and overexpression causing reciprocal effects of depleting or expanding the progenitor pool. Taken together, these data suggest that BAZ1B-mediated dysregulation of the Wnt signaling pathway may at least partially explain the phenotypes observed in WS.

Kosik and his colleagues plan to establish a three-dimensional (spheroid) culture system of functional cortical neurons and astrocytes, which they can experimentally manipulate, in order to assess the effects of 7q11.23 deletion and duplication. The researchers will assess germinal zone maturation, neural precursor migration and gene expression in cultures generated from WS pluripotent stem cells and from stem cells derived from individuals with a 7q11.23 duplication. Findings from this work will help further our understanding of the molecular pathways altered in these disorders.

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