Journal Article

Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition

Robinson, Giles, Singh, Shalini, Roussel, Martine F, Howell, Danielle, Ong, Taren, Kessler, Ketty, Rosmaninho, Pedro, Trivedi, Niraj, Solecki, David J, Raposo, Alexandre ASF, Castro, Diogo S

2016

Overview

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. During the formation of the brain, developing neurons are faced with a logistical problem. After newborn neurons form they must change in shape and move to their final location in the brain. Despite much speculation, little is known about these processes. Neurons mature via the activity of several pathways that control the activity, or expression, of the neuron’s genes. One way of controlling such gene expression is through proteins called transcription factors. At the same time, the developing neurons go through a process called polarization, where different regions of the cell develop different characteristics. However, it was not known how the maturation and polarization processes are linked, or how the developing neurons actively regulate polarization. By studying the developing mouse brain, Singh et al. found that a transcription factor called Zeb1 keeps neurons in a immature state, stopping them from becoming polarized. Further investigation revealed that Zeb1 does this by preventing the production of a group of proteins that helps to polarize the cells. The most common type of malignant brain tumour in children is called a medulloblastoma. Singh et al. analyzed the genes expressed in mice that have a type of medulloblastoma that results from the constant activity of a gene called Sonic Hedgehog in developing neurons. This revealed that these tumour cells contain abnormally high levels of Zeb1, and so do not take on a polarized form. However, artificially restoring other factors that encourage the cells to polarize caused the neurons to mature normally. Further investigation is now needed to find out whether the activity of the Sonic Hedgehog gene regulates Zeb1 activity, and to discover whether inhibiting Zeb1 could prevent brain tumours from developing.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Brain - embryology / Brain cancer / cell adhesion / Cell adhesion & migration / Cell cycle / Cell Differentiation / Cerebellum / Children & youth / Developmental Biology and Stem Cells / Epithelial cells / Gene Expression Regulation, Developmental / Hedgehog protein / Homeobox / Medical research / Medulloblastoma / mesenchymal-epithelial transition / Mesenchyme / Mice / Nervous system / Neural circuitry / Neural stem cells / Neurobiology / Neurogenesis / neuronal differentition / neuronal migration / neuronal polarity / Neurons / Neurons - physiology / Neuroscience / Neurosciences / Observations / PAR polarity complex / Physiological aspects / Polarity / Polarization / Statistical analysis / Zinc Finger E-box-Binding Homeobox 1 - genetics / Zinc Finger E-box-Binding Homeobox 1 - metabolism / Zinc finger proteins