Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A role for primary cilia in glutamatergic synaptic integration of adult-born neurons

Nature Neuroscience volume 15, pages 399–405 (2012)Cite this article

Subjects

Abstract

The sequential synaptic integration of adult-born neurons has been widely examined in rodents, but the mechanisms regulating the integration remain largely unknown. The primary cilium, a microtubule-based signaling center, is essential for vertebrate development, including the development of the CNS. We examined the assembly and function of the primary cilium in the synaptic integration of adult-born mouse hippocampal neurons. Primary cilia were absent in young adult-born neurons, but assembled precisely at the stage when newborn neurons approach their final destination, further extend dendrites and form synapses with entorhinal cortical projections. Conditional deletion of cilia from adult-born neurons induced severe defects in dendritic refinement and synapse formation. Deletion of primary cilia led to enhanced Wnt and β-catenin signaling, which may account for these developmental defects. Taken together, our findings identify the assembly of primary cilia as a critical regulatory event in the dendritic refinement and synaptic integration of adult-born neurons.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Primary cilia assemble in developing adult-born neurons.
Figure 2: Entorhinal cortical innervations of adult-born neurons accompany primary cilia assembly.
Figure 3: Primary cilia deletion caused by expressing dnKif3a severely disrupts functional glutamatergic synapse formation in adult-born neurons.
Figure 4: Primary cilia deletion in adult-born neurons results in defective dendritic refinement.
Figure 5: Altered Wnt and β-catenin signaling activity upon primary cilia deletion regulates the dendritic refinement of adult-born neurons.

Similar content being viewed by others

References

  1. Altman, J. & Das, G.D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335 (1965).

    Article  CAS  PubMed  Google Scholar 

  2. Kempermann, G., Gast, D. & Gage, F.H. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52, 135–143 (2002).

    Article  PubMed  Google Scholar 

  3. Ma, D.K. et al. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat. Neurosci. 13, 1338–1344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhao, C., Deng, W. & Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Ge, S., Pradhan, D.A., Ming, G.L. & Song, H. GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci. 30, 1–8 (2007).

    Article  PubMed  Google Scholar 

  6. Kelsch, W., Sim, S. & Lois, C. Watching synaptogenesis in the adult brain. Annu. Rev. Neurosci. 33, 131–149 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Overstreet Wadiche, L., Bromberg, D.A., Bensen, A.L. & Westbrook, G.L. GABAergic signaling to newborn neurons in dentate gyrus. J. Neurophysiol. 94, 4528–4532 (2005).

    Article  PubMed  Google Scholar 

  10. Esposito, M.S. et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gerdes, J.M., Davis, E.E. & Katsanis, N. The vertebrate primary cilium in development, homeostasis and disease. Cell 137, 32–45 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, J.E. & Gleeson, J.G. Cilia in the nervous system: linking cilia function and neurodevelopmental disorders. Curr. Opin. Neurol. 24, 98–105 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Goetz, S.C. & Anderson, K.V. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331–344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lancaster, M.A. & Gleeson, J.G. The primary cilium as a cellular signaling center: lessons from disease. Curr. Opin. Genet. Dev. 19, 220–229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bisgrove, B.W. & Yost, H.J. The roles of cilia in developmental disorders and disease. Development 133, 4131–4143 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Han, Y.G. & Alvarez-Buylla, A. Role of primary cilia in brain development and cancer. Curr. Opin. Neurobiol. 20, 58–67 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Han, Y.G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat. Neurosci. 11, 277–284 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Breunig, J.J. et al. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc. Natl. Acad. Sci. USA 105, 13127–13132 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Corbit, K.C. et al. Kif3a constrains beta-catenin-dependent Wnt signaling through dual ciliary and non-ciliary mechanisms. Nat. Cell Biol. 10, 70–76 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Szymczak, A.L. et al. Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide–based retroviral vector. Nat. Biotechnol. 22, 589–594 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Bishop, G.A., Berbari, N.F., Lewis, J. & Mykytyn, K. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J. Comp. Neurol. 505, 562–571 (2007).

    Article  PubMed  Google Scholar 

  22. Pazour, G.J. et al. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J. Cell Biol. 151, 709–718 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schneider, L. et al. Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell. Physiol. Biochem. 25, 279–292 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tsai, L.H. & Gleeson, J.G. Nucleokinesis in neuronal migration. Neuron 46, 383–388 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Duan, X. et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130, 1146–1158 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Amaral, D.G., Scharfman, H.E. & Lavenex, P. The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog. Brain Res. 163, 3–22 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Ge, S., Yang, C.H., Hsu, K.S., Ming, G.L. & Song, H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54, 559–566 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kempermann, G., Kuhn, H.G. & Gage, F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Rohatgi, R., Milenkovic, L., Corcoran, R.B. & Scott, M.P. Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc. Natl. Acad. Sci. USA 106, 3196–3201 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Willaredt, M.A. et al. A crucial role for primary cilia in cortical morphogenesis. J. Neurosci. 28, 12887–12900 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishimura, T. et al. Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity. Nat. Cell Biol. 6, 328–334 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Brown, C.L. et al. Kinesin-2 is a motor for late endosomes and lysosomes. Traffic 6, 1114–1124 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Delaval, B., Bright, A., Lawson, N.D. & Doxsey, S. The cilia protein IFT88 is required for spindle orientation in mitosis. Nat. Cell Biol. 13, 461–468 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Robert, A. et al. The intraflagellar transport component IFT88/polaris is a centrosomal protein regulating G1-S transition in non-ciliated cells. J. Cell. Sci. 120, 628–637 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Lie, D.C. et al. Wnt signaling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Maretto, S. et al. Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc. Natl. Acad. Sci. USA 100, 3299–3304 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McDermott, K.M., Liu, B.Y., Tlsty, T.D. & Pazour, G.J. Primary cilia regulate branching morphogenesis during mammary gland development. Curr. Biol. 20, 731–737 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brault, V. et al. Inactivation of the beta-catenin gene by Wnt1-Cre–mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128, 1253–1264 (2001).

    CAS  PubMed  Google Scholar 

  40. Li, F.Q., Mofunanya, A., Fischer, V., Hall, J. & Takemaru, K. Nuclear-cytoplasmic shuttling of Chibby controls beta-catenin signaling. Mol. Biol. Cell 21, 311–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Budnik, V. & Salinas, P.C. Wnt signaling during synaptic development and plasticity. Curr. Opin. Neurobiol. 21, 151–159 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chizhikov, V.V. et al. Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J. Neurosci. 27, 9780–9789 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Masdeu, C., Bernard, V., Faure, H., Traiffort, E. & Ruat, M. Distribution of Smoothened at hippocampal mossy fiber synapses. Neuroreport 18, 395–399 (2007).

    Article  PubMed  Google Scholar 

  44. Yam, P.T., Langlois, S.D., Morin, S. & Charron, F. Sonic hedgehog guides axons through a noncanonical, Src family kinase–dependent signaling pathway. Neuron 62, 349–362 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Yu, X. & Malenka, R.C. Beta-catenin is critical for dendritic morphogenesis. Nat. Neurosci. 6, 1169–1177 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Gao, X., Arlotta, P., Macklis, J.D. & Chen, J. Conditional knockout of beta-catenin in postnatal-born dentate gyrus granule neurons results in dendritic malformation. J. Neurosci. 27, 14317–14325 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rosso, S.B., Sussman, D., Wynshaw-Boris, A. & Salinas, P.C. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat. Neurosci. 8, 34–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Ocbina, P.J., Tuson, M. & Anderson, K.V. Primary cilia are not required for normal canonical Wnt signaling in the mouse embryo. PLoS ONE 4, e6839 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Huang, P. & Schier, A.F. Dampened Hedgehog signaling but normal Wnt signaling in zebrafish without cilia. Development 136, 3089–3098 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Spassky, N. et al. Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev. Biol. 317, 246–259 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank S. Halegoua, M. Kernan, G. Matthews, L. Role and H. Song for critical comments, and F.-Q. Li, J. Rodriguez and Q. Xiong for technical support. This work was supported by grants from the US National Institutes of Health (NS065915 to S.G. and HL107493 to K.-I.T.), the American Heart Association (0930067N to S.G.) and the State University of New York Research Excellence in Academic Health (to S.G.).

Author information

Author notes

  1. Natsuko Kumamoto

    Present address: Present address: Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Suita, Japan.,

  2. Natsuko Kumamoto, Yan Gu and Jia Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, New York, USA

    Natsuko Kumamoto, Yan Gu, Jia Wang, Stephen Janoschka, Joel Levine & Shaoyu Ge

  2. Program in Neuroscience, State University of New York at Stony Brook, Stony Brook, New York, USA

    Stephen Janoschka

  3. Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York, USA

    Ken-Ichi Takemaru

Authors
  1. Natsuko Kumamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen Janoschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken-Ichi Takemaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joel Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shaoyu Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.K. engineered the retroviral constructs. N.K. and J.W. carried out the immunohistochemistry and confocal imaging analysis. Y.G. performed all of the physiology analyses and took some images. S.J. helped analyze some images and edited the manuscript. K.-I.T. helped to characterize the retroviral vectors. S.G. supervised the project. S.G. and J.L. wrote the manuscript. All of the authors read and discussed the manuscript.

Corresponding author

Correspondence to Shaoyu Ge.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 (PDF 4904 kb)

Supplementary Video 1

Three dimensional reconstruction of Z-series confocal images of primary cilia. Shown is a primary cilium image of an adult-born neuron at 21 dpi expressing the dTomato and EGFP-Centrin-2, counterstained for DAPI and immunostained for ACIII (see Methods). (MOV 2018 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumamoto, N., Gu, Y., Wang, J. et al. A role for primary cilia in glutamatergic synaptic integration of adult-born neurons. Nat Neurosci 15, 399–405 (2012). https://doi.org/10.1038/nn.3042

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3042

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing