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Wnt signalling regulates adult hippocampal neurogenesis

Abstract

The generation of new neurons from neural stem cells is restricted to two regions of the adult mammalian central nervous system: the subventricular zone of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus1. In both regions, signals provided by the microenvironment regulate the maintenance, proliferation and neuronal fate commitment of the local stem cell population1. The identity of these signals is largely unknown. Here we show that adult hippocampal stem/progenitor cells (AHPs) express receptors and signalling components for Wnt proteins, which are key regulators of neural stem cell behaviour in embryonic development2. We also show that the Wnt/β-catenin pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche. Overexpression of Wnt3 is sufficient to increase neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of Wnt signalling reduces neurogenesis from AHPs in vitro and abolishes neurogenesis almost completely in vivo. Our data show that Wnt signalling is a principal regulator of adult hippocampal neurogenesis and provide evidence that Wnt proteins have a role in adult hippocampal function.

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Figure 1: Wnt signalling is involved in hippocampal-astrocyte-induced neurogenesis from AHPs.
Figure 2: Wnt3 is sufficient to increase neuronal production from AHP.
Figure 3: Blocking Wnt signalling in vivo suppresses adult hippocampal neurogenesis.
Figure 4: Enhanced Wnt signalling in vivo increases adult hippocampal neurogenesis.

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Acknowledgements

We thank H. Clevers, R. Nusse, R.T. Moon, E. Fuchs, R. Marr and J. Nathans for cDNA and plasmids; S. Piccolo and B. Sosa-Pineda for BATGAL reporter mice; R. Summers, K. Nakashima, T. Kuwabara and H. Suh for discussions and suggestions; M.L. Gage for editorial comments; and L. Kitabayashi for technical assistance. D.C.L. and S.J. are supported in part by the Deutsche Forschungsgemeinschaft (DFG, Germany), S.A.C. was supported by NRSA, L.D. was supported by the Association for Medical Research (FRM, France), A.C. is a recipient of a Telethon postdoctoral fellowship. Additional support was provided by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Max Planck Research Award Program funded by the German Ministry for Education, Science, Research, and Technology, the Lookout Fund, the Christopher Reeves Paralysis Foundation, Defense Advanced Research Projects Agency and Project ALS (to F.H.G.), and from the NINDS and NIA (to H.J.S.). Author Contributions D.C.L. is the leading author. He contributed to the concept, designed and did the experiments, analysed the data, wrote the paper and provided partial financial support. S.A.C. contributed to the concept, designed and did the in vivo loss-of-function experiment, contributed reagents and revised the paper. H.J.S. contributed to the concept and the co-culture experiments. L.D. initiated the study, contributed to the concept and did part of the RT–PCR analysis. H.M. contributed to the co-culture experiments. A.C. generated the LV vectors. E.S.L. did the in situ hybridization. S.J. analysed the BATGAL mice. H.L. and A.R.D. provided technical support and contributed to analysis of the data. F.H.G. is the senior author. He contributed to the concept, analysed the data, revised the manuscript and provided the main financial support.

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Correspondence to Dieter-Chichung Lie or Fred H. Gage.

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Supplementary information

Supplementary Figure Legends

Legends to accompany the Supplementary Figures. (DOC 28 kb)

Supplementary Figure 1

Wnt proteins expressed by AHPs are not sufficient to elicit significant Wnt/β-catenin signalling in AHPs. (PDF 267 kb)

Supplementary Figure 2

Stimulation of Wnt/β-catenin signalling in AHPs by Wnt3. (PDF 176 kb)

Supplementary Figure 3

Wnt3 overexpression does not enhance the generation of glial cells. (PDF 199 kb)

Supplementary Figure 4

Time course of differentiation of AHPs into doublecortin-expressing cells. (PDF 169 kb)

Supplementary Figure 5

Suppression of Wnt//β-catenin signalling in AHPs by dnWnt. (PDF 168 kb)

Supplementary Figure 6

DnWnt overexpression does not increase cell death in vitro or in vivo. (PDF 198 kb)

Supplementary Methods

Detailed, additional description of methods. (DOC 26 kb)

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Lie, DC., Colamarino, S., Song, HJ. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005). https://doi.org/10.1038/nature04108

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