ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development

Wang, Huanhuan; Xiao, Zhao; Zheng, Jiangli; Wu, Jun; Hu, Xiaoling; Yang, Xuerui; Shen, Qin

doi:10.1016/j.celrep.2019.04.081

Cited by 56 publications

(45 citation statements)

References 116 publications

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“…Therefore, the effects of Zeb1 deletion in the brain have so far only been investigated during embryonic development. Two studies have reported that downregulation of ZEB1 expression is necessary for the neuronal commitment of precursor cells, allowing them to gain a neuronal identity while migrating to their maturation destinations in the developing cerebellum and cortex, respectively (Singh, Howell et al 2016, Wang, Xiao et al 2019. This is partially mirrored in the adult hippocampus as we observed a lack of ZEB1 in the neuroblast and granule neuron populations.…”

Section: Discussionsupporting

confidence: 62%

“…Results ZEB1 is a known regulator of stemness in many solid tissues (Goossens, Vandamme et al 2017). Recent studies have shown that ZEB1 functions in embryonic neurogenesis (Singh, Howell et al 2016, Liu, Liu et al 2019, Wang, Xiao et al 2019), and we have previously shown that ZEB1 is crucial for the self-renewal of cancer stem cells in glioblastoma (Siebzehnrubl, Silver et al 2013, Hoang-Minh, Siebzehnrubl et al 2018, Jimenez-Pascual, Hale et al 2019.…”

Section: Zeb1 In Hippocampal Neurogenesismentioning

confidence: 92%

“…ZEB1 can act as either a transcriptional activator or repressor depending on the recruited cofactors (Spaderna, Schmalhofer et al 2008, Rosmaninho, Mukusch et al 2018. ZEB1 expression is crucial for the maintenance of the embryonic radial glial cells in an undifferentiated state, and its downregulation drives the correct maturation and migration of cerebellar and cortical neurons during development (Singh, Howell et al 2016, Liu, Liu et al 2019, Wang, Xiao et al 2019. Zeb1-null mice die perinatally with severe skeletal defects, craniofacial abnormalities, and limb defects, as well as respiratory failure and T cell deficiency; this indicates the importance of ZEB1 in cell polarity (Takagi, Moribe et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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The transcription factor ZEB1 regulates stem cell self-renewal and astroglial fate in the adult hippocampus

Gupta

Errington

Brabletz

et al. 2020

Preprint

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Radial glia-like (RGL) cells persist in the adult mammalian hippocampus where they give rise to new neurons and astrocytes throughout life. Many studies have investigated the process of adult neurogenesis, but factors deciding between neuronal and astroglial fate are incompletely understood. Here, we evaluate the functions of the transcription factor zinc finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells as well as for astroglial lineage specification. Genetic deletion of Zeb1 causes differentiation-coupled depletion of RGL cells resulting in an increase of newborn neurons at the expense of newly generated astrocytes. This is due to a shift towards symmetric cell divisions that consume the RGL cell and generate pro-neuronal progenies. We identify ZEB1 as a regulator of stem cell self-renewal and lineage specification in the adult hippocampus.

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Section: Discussionsupporting

confidence: 62%

Section: Zeb1 In Hippocampal Neurogenesismentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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The transcription factor ZEB1 regulates stem cell self-renewal and astroglial fate in the adult hippocampus

Gupta

Errington

Brabletz

et al. 2020

Preprint

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“…Moreover, while not playing a direct role in the regulation of the BTSC precursor state under our culture conditions, key EMT transcription factors other than SLUG likely play important roles in tumor progression by contributing to essential processes such as invasion and survival and proliferation. Interestingly, ZEB1, the most expressed EMT regulator across our BTSC lines, plays central roles in regulating differentiation and invasion in both NSCs during development and glioma cells [46,47].…”

Section: Discussionmentioning

confidence: 99%

SLUG Directs the Precursor State of Human Brain Tumor Stem Cells

Chesnelong

Hao

Cseh

et al. 2019

Cancers

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In glioblastoma (GBM), brain tumor stem cells (BTSCs) encompass heterogenous populations of multipotent, self-renewing, and tumorigenic cells, which have been proposed to be at the root of therapeutic resistance and recurrence. While the functional significance of BTSC heterogeneity remains to be fully determined, we previously distinguished relatively quiescent stem-like precursor state from the more aggressive progenitor-like precursor state. In the present study, we hypothesized that progenitor-like BTSCs arise from stem-like precursors through a mesenchymal transition and drive post-treatment recurrence. We first demonstrate that progenitor-like BTSCs display a more mesenchymal transcriptomic profile. Moreover, we show that both mesenchymal GBMs and progenitor-like BTSCs are characterized by over-activated STAT3/EMT pathways and that SLUG is the primary epithelial to mesenchymal transition (EMT) transcription factor directly regulated by STAT3 in BTSCs. SLUG overexpression in BTSCs enhances invasiveness, promotes inflammation, and shortens survival. Importantly, SLUG overexpression in a quiescent stem-like BTSC line enhances tumorigenesis. Finally, we report that recurrence is associated with SLUG-induced transcriptional changes in both BTSCs and GBM patient samples. Collectively, our findings show that a STAT3-driven precursor state transition, mediated by SLUG, may prime BTSCs to initiate more aggressive mesenchymal recurrence. Targeting the STAT3/SLUG pathway may maintain BTSCs in a quiescent stem-like precursor state, delaying recurrence and improving survival in GBM.

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“…EMT was important in direct cell fate conversion in addition to reprogramming, embryonic development, and cancer progression [40]. EMT was critical for biological processes involving cell migration, such as gastrulation, neural crest delamination, and invasion and metastasis of carcinoma cells [41,42]. Interplay between autophagy and EMT influences cell fate [43].…”

Section: Discussionmentioning

confidence: 99%

Gynura divaricata Water Extract Presented the Possibility to Enhance Neuronal Regeneration

Kantawong

Saisuwan

Soeratanapant

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Gynura divaricata (GD) is an Asian herb widely used as an alternative medicine and functional food for type 2 diabetes. Diabetic neuropathy is considered as an important complication of diabetic patients. This study focused on neuroregenerative effects of GD for use in the prevention of diabetic neuropathy. GD leaves were cut and boiled in water to mimic real-life cooking. The boiled content was filtered through white gauze and lyophilized to preserve as dried powder. Antioxidant assay was performed using DPPH assays. UHPLC-QTOF-MS/MS was employed to test for important compounds in the extract of these herbs. MTT assay was used to test for cell viability. The extracts at concentration of 250 μg/mL were tested with human gingival cell to observe the change of gene expression. The DPPH assay showed that GD water extract at the concentration of 5000 μg/mL could inhibit DPPH radical for 39.2%. The results showed that 5000 µg of GD water extract contained total phenolic content equivalent to 310.9 µg standard gallic acid. UHPLC-QTOF-MS/MS result found phenolic acids and flavonoids as the main components. Human gingival cells treated with 250 μg/mL of GD water extract for 10 days showed upregulation of some neuronal differentiation markers. Staining with Cdr3 dye confirmed the presentation of neuronal progenitors. The extract at the concentration of 250 μg/mL was also tested with apical papilla cells to screen for change of gene expression by RNA sequencing. The result also showed significant upregulation of alpha-internexin (INA). These results indicated that GD water extract might have an inductive effect for neural regeneration and could be used as functional food and supplementation for the prevention or treatment of diabetic neuropathy. This work provided the basic knowledge for further investigations into the benefits of GD for diabetic neuropathy.

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ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development

Cited by 56 publications

References 116 publications

The transcription factor ZEB1 regulates stem cell self-renewal and astroglial fate in the adult hippocampus

The transcription factor ZEB1 regulates stem cell self-renewal and astroglial fate in the adult hippocampus

SLUG Directs the Precursor State of Human Brain Tumor Stem Cells

Gynura divaricata Water Extract Presented the Possibility to Enhance Neuronal Regeneration

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