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Molecular regulator of normal and pathological neurogenesis

Glioblastoma multiforme (GBM) is a devastating and highly invasive brain tumour. The presence of cancer stem cells renders GBM more resistant to radiation and conventional therapy.
Molecular regulator of normal and pathological neurogenesis
Since the discovery of neural stem cells, there has been particular interest in using them to repair brain damage and to understand neurodevelopmental pathologies. This, however, necessitates detailed mechanistic insight into their maintenance and differentiation. Several lines of evidence suggest that the zinc-finger transcription factor ZEB1, which is implicated in the process of epithelial-to-mesenchymal transition, has an important role in embryonic neural progenitor cells and in tumours of neural origin.

When it comes to GBM, the presence of cancer stem cells is responsible for resistance to therapy and regression. Recent reports suggest that ZEB1 promotes invasion, chemoresistance and tumourigenesis of GBM. However, little is known about the molecular mechanism of ZEB1 activity or its targets.

Scientists on the EU-funded ZEB1 (The transcriptional network of the zinc-finger factor ZEB1 and its function in the embryonic nervous system and glioma development) project employed functional genomics to provide further insight into the role of ZEB1 in neural development and cancer. To this end, they performed gain- and loss-of-function studies in the mouse cerebellum.

Their results showed that ZEB1 was necessary and sufficient to maintain granule neuron progenitors (GNPs) in an undifferentiated state. Genome-wide analysis of ZEB1 target genes in these cells showed that ZEB1 directly binds and represses the transcription of multiple polarity and cell adhesion genes. When researchers restored the expression of these genes in GNPs, they rescued the defects in GNP differentiation.

Furthermore, scientists found ZEB1 to be highly expressed in GBM cancer stem cells. To identify its mode of action, they knocked down ZEB1 and discovered that it was associated with both activation and repression of gene expression. This dual role could take place in the same cellular context and resulted from two distinct modes of recruitment to regulatory regions.

Overall, the findings of the ZEB1 study provided fundamental insight into the role of ZEB1 in neurogenesis and GBM. ZEB1 emerges as an important regulator of neuronal differentiation and GBM outcome, and could thus be exploited therapeutically.

Related information

Keywords

Glioblastoma multiforme, brain tumour, cancer stem cells, ZEB1, neuron progenitors
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