Transcription factor dynamics underlying adult hippocampal neurogenesis

Throughout life, the dentate gyrus generates new granule cells (abGCs) that integrate into adult circuits. Using single-nuclei RNAseq of distinct abGCs cohorts, combined with differential gene expression, pseudotime and transcription factors (TFs) regulon analysis, we identified four cellular states: quiescent radial glia-like neural stem cells, proliferative progenitors, immature and mature abGCs. We propose that transitions between states are governed by stage-specific transcriptional regulators. To probe this, we manipulated key TFs to unravel mechanisms underlying abGCs differentiation and integration. Foxo1, Hlf and Tef are expressed in quiescent stem cells, downregulated during development, and switched back on in mature abGCs. This dynamic suggests they act as transcriptional brakes, where initial repression allows growth while reactivation stabilizes a mature homeostatic phenotype. We overexpressed (oe) each TF in abGCs using retrovirus and assessed morphology by confocal microscopy. OeFoxo1-abGCs exhibited an initial transient reduction in dendritic complexity, restored upon maturation. In contrast, oeHlf-abGCs and oeTef-abGCs displayed impaired dendritic growth, preventing neurons from achieving normal morphological complexity. These structural changes may underlie integration dynamics, currently under study. Therefore, we propose that Foxo1, Hlf and Tef tightly control dendritic arborization, acting as homeostatic brakes to stabilize mature neuronal structure.