Abstract
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.
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Acknowledgements
We thank T. Ohtake for assistance with animal care and supporting our in vivo experiments. We thank M. Namihira and J. Kohyama for assistance in obtaining immunostaining data, E. Mosser for the constitutively active β-catenin construct, and G. Canettieri and M. Montminy for HDAC1. We thank A. Huynh for help with immunohistochemical analysis. We are grateful for the technical assistance of B. Miller and to M.L. Gage for editorial comments. T.K., M.W. and M.A. were supported by various grants from National Institute of Advanced Industrial Science and Technology. T.K. was partly supported by the Grant-in-Aid for Exploratory Research. F.H.G. was supported by grants from the US National Institutes of Health (MH082070) and the G. Harold and Leila Y. Mathers Charitable Foundation.
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T.K., J.H., A.M., K.N. and F.H.G. conceptualized and designed the study. T.K., J.H., A.M. and F.H.G. analyzed the data. T.K. conducted the experiments with assistance from M.W., J.H. and L.M. G.Y. and A.M. conducted the bioinformatics analysis. A.M. helped design the LINE-1 plasmid constructs, D.C.L. helped with the Wnt plasmid design and constructs, and M.W. designed the shRNA construct. M.A. contributed reagents and analytical tools. T.K. wrote the paper with comments from all of the authors.
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Kuwabara, T., Hsieh, J., Muotri, A. et al. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci 12, 1097–1105 (2009). https://doi.org/10.1038/nn.2360
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DOI: https://doi.org/10.1038/nn.2360
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