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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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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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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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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DOI: https://doi.org/10.1038/nn2059
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