The effects of DLL3 in axial skeletal development and glioma
Loading...
Date
2014-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
The Notch pathway is critical for normal development of the skeleton and nervous system.
Dysregulation of Notch can also promote glioma, cancer of the glial cells. Tight regulation of
Notch is achieved by modulating pathway activity through inhibitory ligands (like DLL3) and/or
glycosyltransferases that affect receptor-ligand interactions (like Lunatic Fringe). In most
contexts, increased Lfng causes an increase in Notch activity, while Dll3 expression causes a
decrease in Notch activity. Our project looked at this modulation in two systems: axial skeletal
development and glioma cells. In the presomitic mesoderm (PSM), loss of Lfng increases Notch
activity while a loss of Dll3 causes a decrease in Notch activity. Examination of skeletal
phenotypes and Notch activation patterns in double knockout mice shows that the Dll3-null
phenotype is epistatic to the Lfng-null phenotype in the posterior PSM, suggesting that in a
molecular clock-dependent setting, LFNG acts through DLL3 to inhibit Notch activation.
However, in the anterior PSM, LFNG and DLL3 work through different pathways to regulate
Notch. In contrast, in glioma Notch signaling maintains glioma stem cells, which worsen
outcomes. Increased Dll3 expression in glioma tumors leads to better prognosis, suggesting
DLL3 may inhibit Notch activity. To study this hypothesis, we used Luciferase assays in glioma
cells stably transfected with a luciferase gene under the control of a Notch-dependent promoter,
as well as MTS viability assays. We found that increasing Dll3 expression decreases Notch
signaling, but does not affect cell viability (a Notch-independent phenotype). DLL3 appears to
be a promising inhibitor of Notch activity in glioma cells, suggesting it could be targeted in
future treatment options. We have found that regulation of Notch is highly context dependent,
both in development and disease.
Description
Honorable Mention at 2014 Denman Undergraduate Research Forum
Keywords
DLL3, Notch, skeletal development, glioma, Lunatic Fringe