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

Bhavana Gupta,Adam C Errington,Vasileios Eftychidis,Marc P Stemmler,David Petrik,Florian A Siebzehnrubl,Thomas Brabletz,Ana Jimenez-Pascual,Simone Brabletz

doi:10.1016/j.celrep.2021.109588

Bhavana Gupta, Adam C Errington + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109588

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Abstract

SummaryRadial glia-like (RGL) stem cells persist in the adult mammalian hippocampus, where they generate new neurons and astrocytes throughout life. The process of adult neurogenesis is well documented, but cell-autonomous factors regulating neuronal and astroglial differentiation 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. Genetic deletion of Zeb1 causes a shift toward symmetric cell division that consumes the RGL cell and generates pro-neuronal progenies, resulting in an increase of newborn neurons and a decrease of newly generated astrocytes. We identify ZEB1 as positive regulator of the ets-domain transcription factor ETV5 that is critical for asymmetric division.

Highlights

Neural stem cells persist in the adult hippocampus across many mammalian species (Gage, 2019; Ming and Song, 2011), including humans (Coras et al, 2010; Kempermann et al, 2018)
We found that zinc-finger E-box binding homeobox 1 (ZEB1) is necessary for the maintenance of activated Radial glia-like (RGL) cells; loss of Zeb1 led to a differentiation-coupled depletion of the RGL pool accompanied by a transient increase in neurogenesis and a loss of subgranular zone (SGZ)-derived astrocytes
Recent studies showed that ZEB1 functions in embryonic neurogenesis (Liu et al, 2019; Singh et al, 2016; Wang et al, 2019), and we previously found that ZEB1 is crucial for the self-renewal of glioblastoma cancer stem cells (HoangMinh et al, 2018; Jimenez-Pascual et al, 2019; Siebzehnrubl et al, 2013)

Summary

SUMMARY

Radial glia-like (RGL) stem cells persist in the adult mammalian hippocampus, where they generate new neurons and astrocytes throughout life. The process of adult neurogenesis is well documented, but cellautonomous factors regulating neuronal and astroglial differentiation are incompletely understood. 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. Genetic deletion of Zeb causes a shift toward symmetric cell division that consumes the RGL cell and generates pro-neuronal progenies, resulting in an increase of newborn neurons and a decrease of newly generated astrocytes. We identify ZEB1 as positive regulator of the ets-domain transcription factor ETV5 that is critical for asymmetric division

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