A human neurodevelopmental model for Williams syndrome

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 DESCRIPTION (provided by applicant): The main goal of this proposal is to define the contribution of specific genes to cellular and molecular phenotypes relevant to William's syndrome (WS). WS is a genetic neurodevelopmental disorder characterized by an unusual hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. WS is caused by a hemizygous deletion of approximately 25 genes in chromosome band 7q11.23. Treatment for this disorder is entirely symptomatic: there are no curative or disease modifying therapies. We used cellular reprogramming technologies to generate induced pluripotent stem cells (iPSCs) from WS and typically developing (TD) individuals. Our data revealed increased apoptosis in WS neural progenitor cells (NPCs) and a higher complexity of neuronal dendrites in WS cortical layer V/VI neurons. We also used structural imaging of the brains of living subjects and found that WS showed decreased cortical surface area compared to TD. Additionally, we performed a morphometric analysis of cortical neurons from postmortem human brains and, similar to the iPSC-derived neurons, we also revealed longer total dendrites and increased number of spines in WS. Thus, we hypothesize that deletion of certain genes in the WS region can lead too specific defects in human NPCs and neurons. To link genes to cellular and molecular phenotypes, we propose the following specific aims: Aim 1: Determine the impact of the FZD9 and GTF2I deletion cellular and molecular phenotypes in WS and Aim 2: Measure cortical neuronal morphology and density in WS and TD postmortem adult and developing brain tissue. These experiments will allow us to determine the impact of the FZD9 and GTF2I deletions on the WS cellular and molecular phenotypes. Our findings will connect these two genes to specific cellular defects that may contribute to WS social behaviors. Direct comparison of cellular phenotypes in vitro will come from postmortem brain tissue quantification. This information will be important not only for WS, but also for other developmental human conditions affecting the human social brain, such as autism spectrum disorders.