Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity

Abstract

As a master regulator of the dynamic process of adult neurogenesis, timely expression and regulation of the orphan nuclear receptor Tailless (Tlx) is essential. However, there is no study yet to directly investigate the essential role of precise spatiotemporal expressed Tlx. Here, we generated a conditional gain of Tlx expression transgenic mouse model, which allowed the extended Tlx expression in neural stem cells (NSCs) and their progeny by mating with a TlxCreERT2 mouse line. We demonstrate that extended expression of Tlx induced the impaired generation of mature neurons in adult subventricular zone and subgranular zone. Furthermore, we elucidated for the first time that this mutation decreased the endogenous expression of Sox2 by directly binding to its promoter. Restoration experiments further confirmed that Sox2 partially rescued these neuron maturation defects. Together, these findings not only highlight the importance of shutting-off Tlx on time in controlling NSC behavior, but also provide insights for further understanding adult neurogenesis and developing treatment strategies for neurological disorders.