Investigating the role of ZEB1 in adult hippocampal neurogenesis

Neural stem cells (NSCs) persist within neurogenic niches in the adult mammalian central nervous system (CNS) and generate neurons throughout the lifespan of an animal. This neurogenesis constitutes a step-wise process that is governed by cell intrinsic transcriptional regulators that function in synchrony in NSCs as well as successive progenies at each step. Several transcriptional regulators of adult neurogenesis have been identified, most of which are tissue-specific. Whether broader-functioning ‘master regulators’ that govern stem cell function across multiple tissues also impact on adult NSCs is incompletely understood. The transcription factor zinc finger E-box binding homeobox 1 (ZEB1) is a known regulator of stem cell self-renewal in many epithelial tissues, but also functions to maintain NSCs in an undifferentiated state during embryonic CNS development. Whether ZEB1 also functions in adult neurogenesis remains unclear and is addressed here. A novel transgenic mouse model to target ZEB1 expression in astrocytes and NSCs was used to investigate self-renewal and differentiation of adult NSCs in the hippocampus. Inducible and conditional deletion of Zeb1 in mice resulted in the precocious differentiation of hippocampal NSCs into neurons and a gradual depletion of the stem cell pool. Newborn neurons showed a greater survival during the process of maturation, and behavioural studies suggested that this amplification in granule neurons did not alter the cognitive function of Zeb1-deficient mice. Contrastingly, astrocyte numbers in the dentate gyrus were reduced following the ablation of Zeb1. This indicates that ZEB1 regulates both stem cell self-renewal and cell fate in the adult brain. Dissecting how ZEB1 regulates adult neurogenesis will increase our understanding of the basic mechanisms underlying stem cell maintenance in the adult brain. This will set the foundation for future work to identify mechanistic targets of ZEB1 in adult neurogenesis