Investigating the Role of Transcription Factor 4 (Tcf4) In Adult Neural Stem Cells

Abstract

Elucidating the role of the transcription factor Tcf4 in adult neural stem cells (NSCs), crucial for neurogenesis in specific brain regions, was the primary focus of this study. Although Tcf4 is recognized for its significance in embryonic brain development and its association with certain neurodevelopmental disorders, its function in adult neurogenesis has remained ambiguous. Through selective deletion of Tcf4 in cultured NSCs and in mice, it was revealed that its absence not only diminished proliferation and self-renewal abilities but also unexpectedly activated genes linked to inflammation and myeloid cell development. This suggests a critical role for Tcf4 in suppressing these genes to maintain NSC fate. The investigation extended to exploring the relevance of Tcf4 regulation in response to physiological conditions, particularly stress. While stress is known to negatively impact adult neurogenesis, the underlying mechanisms are poorly understood. Initial findings indicated a reduction in Tcf4 levels in adult NSCs during phases associated with spatial memory deficits, suggesting a potential link between Tcf4 and stress response. Transcriptome analyses of NSC cultures from stressed mice further elucidated the molecular changes induced by stress-induced Tcf4 downregulation, revealing a pattern of upregulated inflammatory genes akin to the effects observed with Tcf4 deletion. Overall, these findings illuminate a previously unrecognized role of adult NSCs in responding to adverse physiological conditions such as stress, emphasizing the critical role of Tcf4 in regulating their function.