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Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells

Nature Neuroscience volume 11, pages 277–284 (2008)Cite this article

Abstract

Neural stem cells that continue to produce neurons are retained in the adult hippocampal dentate gyrus. The mechanisms by which embryonic neural progenitors expand and transform into postnatal neural stem cells, an essential process for the continual production of neurons throughout life, remain unknown. We found that radial astrocytes, the postnatal progenitors in the dentate gyrus, failed to develop after embryonic ablation of ciliary genes or Smoothened (Smo), an essential component for Sonic hedgehog (Shh) signaling. Postnatal dentate neurogenesis failed in these mutant mice, and the dentate gyrus became severely hypotrophic. In contrast, expression of a constitutively active Smo (SmoM2-YFP) resulted in a marked expansion of the dentate gyrus. Double-mutant analyses suggested that both wild-type Smo and SmoM2-YFP function through the primary cilia. We conclude that Shh signaling, acting through the primary cilia, has a critical role in the expansion and establishment of postnatal hippocampal progenitors.

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Figure 1: Ablation of Kif3a removes primary cilia and disrupts germinal activity in the adult dentate gyrus.
Figure 2: hGFAP::Cre; Kif3afl/fl mice fail to expand GNPs and to establish adult stem cells in the dentate gyrus.
Figure 3: Ift88orpk/orpk mice show decreased proliferation of GNPs in the dentate gyrus.
Figure 4: hGFAP::Cre; Kif3afl//fl mice show defective Shh signaling in the dentate gyrus.
Figure 5: hGFAP::Cre; Smofl/fl mice show defects in dentate gyrus development that resemble hGFAP::Cre; Kif3afl/fl mice.
Figure 6: Primary cilia are required for the function of both wild-type and constitutively active Smo.

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Acknowledgements

We are grateful to L.S. Goldstein for providing us with the Kif3a conditional mutant mice, N. Murcia for Ift88orpk mice, and J. Reiter and D. Rowitch for Smo and SmoM2 conditional mutant mice and PtclacZ/+ mice. We thank R. Ihrie, D. Lim, S. Pleasure, J. Reiter and C. Yaschine on the manuscript. The work was supported by a Mark Linder/American Brain Tumor Association Fellowship to Y.-G.H. and by grants (NS28478 and HD32116) from the US National Institutes of Health and a grant from the Goldhirsh foundation to A.A.-B. N.S. was supported by the Human Frontier Science Program and the Agence Nationale de la Recherche. Confocal microscopy at Diabetes Endocrinology Research Center Microscopy and Imaging Core was supported by an US National Institute of Health grant (P30 DK063720).

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Authors and Affiliations

  1. Department of Neurological Surgery, Institute for Regeneration Medicine, University of California San Francisco, San Francisco, 94143, California, USA

    Young-Goo Han & Arturo Alvarez-Buylla

  2. Université Pierre and Marie Curie-Paris 6, IFR des Neurosciences, Hôpital Pitié-Salpêtrière, INSERM, U711, F-75013, Paris, France

    Nathalie Spassky & Andrea Aguilar

  3. Laboratorio de Morfologia Celular, Unidad asociada Universidad de Valencia and Centro de Investigacion Principe Felipe, Valencia, 46100, Spain

    Miriam Romaguera-Ros & Jose-Manuel Garcia-Verdugo

  4. CNRS UMR7622, Université Pierre et Marie Curie, 9 Quai Saint Bernard, Paris, 75005, France

    Sylvie Schneider-Maunoury

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Contributions

Y.-G.H. designed and performed most of the experiments. M.R.-R. and J.-M.G.-V. carried out the electron microscopic analyses. N.S. assisted with the initial analysis of hGFAP::Cre; Kif3afl/fl mice. N.S. and A.A. analyzed the Ftm−/− mice. S.S.-M. provided the Ftm−/− mice. A.A.-B. supervised the project. Y.-G.H. and A.A.-B. wrote the manuscript.

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Correspondence to Arturo Alvarez-Buylla.

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Han, YG., Spassky, N., Romaguera-Ros, M. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11, 277–284 (2008). https://doi.org/10.1038/nn2059

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