Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
- St. Jude Children's Research Hospital, United States
- Universite Denis Diderot (Paris VII), France
- Instituto Gulbenkian de Ciência Oeiras, Portugal
- Instituto Gulbenkian de Ciência, Portugal
- St jude Children's Research Hospital, United States
Abstract
In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers.
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Ethics
Animal experimentation: All mouse lines were maintained in standard conditions in accordance with guidelines established and approved by Institutional Animal Care and Use Committee at St. Jude Children's Research Hospital (protocol number = 483).
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© 2016, Singh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
eLife 5:e12717.
https://doi.org/10.7554/eLife.12717
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