A human neurodevelopmental model for Williams syndrome

Nature. 2016 Aug 18;536(7616):338-43. doi: 10.1038/nature19067. Epub 2016 Aug 10.

Abstract

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Apoptosis
  • Brain / pathology*
  • Calcium / metabolism
  • Cell Differentiation
  • Cell Shape
  • Cellular Reprogramming
  • Cerebral Cortex / pathology
  • Chromosomes, Human, Pair 7 / genetics
  • Dendrites / pathology
  • Female
  • Frizzled Receptors / deficiency
  • Frizzled Receptors / genetics
  • Haploinsufficiency / genetics
  • Humans
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Models, Neurological
  • Neural Stem Cells / pathology
  • Neurons / pathology
  • Phenotype
  • Reproducibility of Results
  • Synapses / pathology
  • Williams Syndrome / genetics
  • Williams Syndrome / pathology*
  • Young Adult

Substances

  • FZD9 protein, human
  • Frizzled Receptors
  • Calcium