Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis

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Abstract
This study shows that adult neurogenesis requires canonical Wnt signaling to trigger transcription of pro-neural NeuroD1. Wnt signaling activates β-catenin, which in complex with TCF/LEF displaces the repressor Sox2 from a previously unknown combined Sox/LEF element in the Neurod1 promoter. Similar Sox/LEF elements activated by Wnt signaling were found in LINE-1 retrotransposons. In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.