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

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.DOI: http://dx.doi.org/10.7554/eLife.12717.001

Zeb1 potentiates genome‐wide gene transcription with Lef1 to promote glioblastoma cell invasion

“…Genome-wide mapping of Zeb1 binding profile by ChIP-seq identified 6,879 binding events (P < 10E À10 ), associated with 4,430 unique genes following a nearest gene annotation (Tables EV1 and EV2). Binding events were found at close vicinity to previously identified Zeb1 repressed genes associated with epithelial cell polarity, such as Pard6b, Crb3, or Cdh1 ( Fig 1D) (Eger et al, 2005;Aigner et al, 2007;Singh et al, 2016). Most binding events occur within introns or intergenic regions and at great distances from TSSs, consistent with binding predominantly to distal enhancers ( Fig 1E and F).…”

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

“…ZEB1 expression is high in stem cell-rich embryonic brain but fades during maturation (Koch et al, 2016). ZEB1 controls invasion of human NSC of the SVZ (Kahlert et al, 2015), proliferation of spinal cord stem cells of adult mice (Sabourin et al, 2009), and restricts differentiation of murine granular neuron precursors (GNP) (Singh et al, 2016). Moreover, transforming fetal NSC into invasive tumorigenic cells leads to the induction of an MT signature featuring high SNAI1 expression (Mao et al, 2013).…”

“…Hypoxia induces MT in MB cells by activating SNAI1, vimentin, and N-cadherin (Gupta et al, 2011). Moreover, ZEB1 expression is high in SHH-MB and inhibits granular zone exit, which eventually contributes to tumor formation (Singh et al, 2016).…”

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells

“…As ZEB1 expression is suppressed by pRB-E2F1 complex (Liu et al., 2007), inactivation of pRB promotes its expression, leading to repression of E-cadherin (Peinado et al., 2007) and a subsequent repression of epidermal markers such as keratins (Figures 3G, 3H, and 5). ZEB1 was also shown to play a key role in nervous system development in vivo (Liu et al., 2008, Singh et al., 2016b), mirrored in our model by an upregulation of its neural-related targets (Figure 3I). Together, these data provide a plausible model for the shift between two ectodermal derivatives (Figure 5).…”