Brn4 promotes the differentiation of radial glial cells into neurons by inhibiting CtBP2.

ABSTRACT

Neural stem cells (NSCs) are pluripotent cells that are capable of differentiating into neurons and considered as the most promising cell source for cell replacement therapy. However, the difficulty in inducing neuronal differentiation and maturation from NSCs is a major challenge for their clinical application. Clarifying the molecular mechanisms underlying the neuronal differentiation of NSCs can provide a basis for expanding their uses. Brain 4 (Brn4) is a member of the POU domain family of transcription factors and can induce the neuronal differentiation of NSCs, but its precise function in NSCs is unclear. To address this question, in this study we isolated and expanded radial glial cells (RGCs), a type of NSC, from the cerebral cortex of 14-day embryonic rats and used lentivirus carrying the human Brn4 gene to overexpress Brn4 in these cells. This induced the differentiation of RGCs into neurons and inhibited the expression of C-terminal binding protein 2 (CtBP2), a transcriptional co-repressor. CtBP2 overexpression in RGCs suppressed their differentiation into neurons, whereas CtBP2 knockdown had the opposite effect. These results indicated that Brn4 promoted the neuronal differentiation of NSCs via inhibition of CtBP2 and is a potential tool for generating neurons in cell replacement therapy of neurodegenerative diseases and brain injury.