β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas
- 13 April 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (18), 6963-6968
- https://doi.org/10.1073/pnas.1118754109
Abstract
Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of β-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active--but dysregulated--in astrocytomas. Inhibition of β-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain.Keywords
This publication has 41 references indexed in Scilit:
- Missense mutations in the NF2 gene result in the quantitative loss of merlin protein and minimally affect protein intrinsic functionProceedings of the National Academy of Sciences, 2011
- Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-CblProceedings of the National Academy of Sciences of the United States of America, 2010
- A Reaction-Diffusion Model of the Cadherin-Catenin System: A Possible Mechanism for Contact Inhibition and Implications for TumorigenesisBiophysical Journal, 2010
- Molecular dissection of reactive astrogliosis and glial scar formationTrends in Neurosciences, 2009
- Wnt signaling in development and diseaseNeurobiology of Disease, 2009
- Phospho-regulation of β-Catenin Adhesion and Signaling FunctionsPhysiology, 2007
- In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitroNature Protocols, 2007
- Astrocyte activation and reactive gliosisGlia, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Purification of a pluripotent neural stem cell from the adult mouse brainNature, 2001