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PMID: 27509850 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A human neurodevelopmental model for Williams syndrome.

Nature ·Vol. 536 ·No. 7616 ·2016-00-18 ·Pages 338-43

Chailangkarn T, Trujillo CA, Freitas BC, Hrvoj-Mihic B, Herai RH, Yu DX, Brown TT, Marchetto MC, Bardy C, McHenry L, Stefanacci L, Järvinen A, Searcy YM, DeWitt M, Wong W, Lai P, Ard MC, Hanson KL, Romero S, Jacobs B, Dale AM, Dai L, Korenberg JR, Gage FH, Bellugi U, Halgren E, Semendeferi K, Muotri AR

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.

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,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,pathology Young Adult
Chemicals
FZD9 protein, human Frizzled Receptors Calcium
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Chailangkarn Thanathom
Trujillo Cleber A
Freitas Beatriz C
Hrvoj-Mihic Branka
Herai Roberto H
Yu Diana X
Brown Timothy T
Marchetto Maria C
Bardy Cedric
McHenry Lauren
Stefanacci Lisa
Järvinen Anna
Searcy Yvonne M
DeWitt Michelle
Wong Wenny
Lai Philip
Ard M Colin
Hanson Kari L
Romero Sarah
Jacobs Bob
Dale Anders M
Dai Li
Korenberg Julie R
Gage Fred H
Bellugi Ursula
Halgren Eric
Semendeferi Katerina
Muotri Alysson R
Conflict of Interest

The authors declare no competing financial interests.

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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature19067
Published
2016-00-18
Epub
2016-00-10
Pages
338-43
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4995142
Subset
IM
Grants
NIH HHS · 1-DP2-OD006495-01 · United States
PHS HHS · P01 NICHD033113 · International
NIMH NIH HHS · U19MH107367 · United States
NIH HHS · DP2 OD006495 · United States
NIMH NIH HHS · R01 MH103134 · United States
NIMH NIH HHS · R01 MH100175 · United States
NIMH NIH HHS · R01 MH094753 · United States
NIMH NIH HHS · T32 MH020002 · United States
NIMH NIH HHS · R01MH095741 · United States
NIDCD NIH HHS · T32 DC007361 · United States
NIMH NIH HHS · U19MH106434 · United States
NIMH NIH HHS · R56 MH109587 · United States
NIMH NIH HHS · U19 MH107367 · United States
NIMH NIH HHS · R01MH103134 · United States
NIMH NIH HHS · R01MH094753 · United States
External Links
PubMed source DOI: 10.1038/nature19067 PMC Full Text View journal details
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