The Impact of CASK on Canonical WNT Signaling in Human Cortical Induced Excitatory Neurons

Presenter

Yarah Kalae

Campus

UMass Amherst

Sponsor

ChangHui Pak, Department of Biochemistry and Molecular Biology, UMass Amherst

Schedule

Session 5, 3:30 PM - 4:15 PM [Schedule by Time][Poster Grid for Time/Location]

Location

Poster Board A57, Campus Center Auditorium, Row 3 (A41-A60) [Poster Location Map]

Abstract

Early brain formation and development involves precise coordination of signaling transduction and transcriptional output which determine cell fate and brain structure. Disruption in these processes can lead to a broad range of neurodevelopmental disorders (NDDs) including schizophrenia and Autism Spectrum disorders (ASDs). Here, we use induced cortical excitatory neurons (iNs) differentiated from human pluripotent stem cells to study calcium/calmodulin dependent serine protein kinase (CASK) and its role in NDD establishment. CASK is a synaptic scaffolding molecule that has been shown to be important for proper neurotransmitter release and neurogenesis. CASK loss-of-function mutations are associated with ASD and X-linked intellectual disorder, however it is unclear how CASK function leads to the observed NDDs. Bulk-RNA sequencing of CASK KO iNs demonstrated upregulated gene expression of the canonical WNT/β-catenin pathway components, leading to the idea that CASK normally regulates WNT/β-catenin activity in iNs. Here we expand upon this finding using biochemical approaches to show modifications in the protein-level characteristics of β-catenin, notably a reduction in post-translational modifications, heightened nuclear localization, and an increase in the expression of active β-catenin in CASK-KO iNs. Collectively, these data further support the WNT hyperactivity observed at the transcriptional level. Future experiments will focus on elucidating the mechanism through which CASK influences WNT signaling. Ultimately, these results will inform on the mechanisms through which CASK drives NDDs paving the way for the development of various therapeutic targeting strategies. 

Keywords

Neurodevelopmental disorders , CASK gene , IPSC model

Research Area

Neuroscience and Cognitive Science

SIMILAR ABSTRACTS (BY KEYWORD)