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:

Nuclear Notch1 signaling and the regulation of dendritic development

Nature Neuroscience volume 3, pages 30–40 (2000)Cite this article

Abstract

To understand the function of Notch in the mammalian brain, we examined Notch1 signaling and its cellular consequences in developing cortical neurons. We found that the cytoplasmic domain of endogenous Notch1 translocated to the nucleus during neuronal differentiation. Notch1 cytoplasmic-domain constructs transfected into cortical neurons were present in multiple phosphorylated forms, localized to the nucleus and could induce CBF1-mediated transactivation. Molecular perturbation experiments suggested that Notch1 signaling in cortical neurons promoted dendritic branching and inhibited dendritic growth. These observations show that Notch1 signaling to the nucleus exerts an important regulatory influence on the specification of dendritic morphology in 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: Notch1 expression in the developing cortex.
Figure 2: The subcellular localization of Notch1 changes as cells migrate from the ventricular zone to the cortical plate.
Figure 3: Distribution of Notch1 in cortical cells in culture.
Figure 4: Neuronal differentiation is associated with a relative increase in nuclear Notch1 immunofluorescence.
Figure 5: Characterization of nuclear forms of Notch1.
Figure 6: Notch1 can induce transactivation via CBF1 binding sites in cortical neurons.
Figure 7: Notch1 induces gene expression via the neuron-specific enolase (NSE) promoter.
Figure 8: Effects of altering Notch1 signaling on dendritic morphology.
Figure 9: Effects of Notch1 antisense oligonucleotide treatment on dendritic morphology.

Similar content being viewed by others

References

  1. Greenwald, I. & Rubin, G. M. Making a difference: the role of cell–cell interactions in establishing separate identities for equivalent cells. Cell 68, 271–281 (1992).

    Article  CAS  Google Scholar 

  2. Ghysen, A., Dambly-Chaudiere, C., Jan, L. Y. & Jan, Y. N. Cell interactions and gene interactions in peripheral neurogenesis. Genes Dev. 7, 723–733 ( 1993).

    Article  CAS  Google Scholar 

  3. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Notch signaling. Science 268 , 225–232 (1995).

    Article  CAS  Google Scholar 

  4. Kimble, J. & Simpson, P. The lin-12/Notch signaling pathway and its regulation. Annu. Rev. Cell Dev. Biol. 13, 333–361 (1997).

    Article  CAS  Google Scholar 

  5. Greenwald, I. Lin-12/Notch signaling: lessons from worms and flies. Genes Dev. 12, 1751–1762 ( 1998).

    Article  CAS  Google Scholar 

  6. Pan, D. & Rubin, G. M. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90, 271 –280 (1997).

    Article  CAS  Google Scholar 

  7. Blaumueller, C. M., Qi, H., Zagouras, P. & Artavanis-Tsakonas, S. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 90, 281–291 (1997).

    Article  CAS  Google Scholar 

  8. Logeat, F. et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc. Natl. Acad. Sci. USA 95, 8108–8112 (1998).

    Article  CAS  Google Scholar 

  9. Kidd, S., Lieber, T. & Young, M. W. Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev. 12, 3728–3740 ( 1998).

    Article  CAS  Google Scholar 

  10. Fortini, M. E. & Artavanis-Tsakonas, S. The suppressor of hairless protein participates in notch receptor signaling. Cell 79, 273–282 ( 1994).

    Article  CAS  Google Scholar 

  11. Lecourtois, M. & Schweisguth, F. The neurogenic Suppressor of Hairless DNA-binding protein mediates the transcriptional activation of the Enhancer of split Complex genes triggered by Notch signaling. Genes Dev. 9, 2598–2608 (1995).

    Article  CAS  Google Scholar 

  12. Jarriault, S. et al. Signalling downstream of activated mammalian Notch. Nature 377, 355–358 ( 1995).

    Article  CAS  Google Scholar 

  13. Tamura, K. et al. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr. Biol. 5, 1416–1423 (1995).

    Article  CAS  Google Scholar 

  14. Hsieh, J. J. et al. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol. Cell. Biol. 16, 952–959 (1996).

    Article  CAS  Google Scholar 

  15. Lu, F. M. & Lux, S. E. Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1–responsive element. Proc. Natl. Acad. Sci. USA 93, 5663–5667 (1996).

    Article  CAS  Google Scholar 

  16. Kopan, R., Schroeter, E. H., Weintraub, H. & Nye, J. S. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc. Natl. Acad. Sci. USA 93, 1683–1688 ( 1996).

    Article  CAS  Google Scholar 

  17. Struhl, G. & Adachi, A. Nuclear access and action of Notch in vivo. Cell 93, 649– 660 (1998).

    Article  CAS  Google Scholar 

  18. Schroeter, E. H., Kisslinger, J. A. & Kopan, R. Notch1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386 (1998).

    Article  CAS  Google Scholar 

  19. Lecourtois, M. & Schweisguth, F. Indirect evidence for Delta-dependent intracellular processing of Notch in Drosophila embryos. Curr. Biol. 8, 771– 774 (1998).

    Article  CAS  Google Scholar 

  20. Coffman, C., Harris, W. & Kintner, C. Xotch, the Xenopus homolog of Drosophila notch. Science 249, 1438– 1441 (1990).

    Article  CAS  Google Scholar 

  21. Coffman, C. R., Skoglund, P., Harris, W. A. & Kintner, C. R. Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell 73, 659– 671 (1993).

    Article  CAS  Google Scholar 

  22. Chitnis, A., Henrique, D., Lewis, J., Ish-Horowicz, D. & Kintner, C. Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta. Nature 375, 761–766 ( 1995).

    Article  CAS  Google Scholar 

  23. Dorsky, R. I., Rapaport, D. H. & Harris, W. A. Xotch inhibits cell differentiation in the Xenopus retina. Neuron 14, 487– 496 (1995).

    Article  CAS  Google Scholar 

  24. Austin, C. P., Feldman, D. E., Ida, J. A. Jr. & Cepko, C. L. Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch. Development 121 , 3637–3650 (1995).

    CAS  PubMed  Google Scholar 

  25. Weinmaster, G., Roberts, V. J. & Lemke, G. A homolog of Drosophila Notch expressed during mammalian development. Development 113, 199–205 (1991).

    CAS  PubMed  Google Scholar 

  26. del Amo, F. F. et al. Expression pattern of Motch, a mouse homologue of Drosophila Notch, suggests an important role in early postimplantation mouse development. Development 115, 737– 744 (1992).

    CAS  PubMed  Google Scholar 

  27. Reaume, A. G., Conlon, R. A., Zirngibl, R., Yamaguchi, T. P. & Rossant, J. Expression analysis of a Notch homologue in the mouse embryo. Dev. Biol. 154, 377 –387 (1992).

    Article  CAS  Google Scholar 

  28. Weinmaster, G., Roberts, V. J. & Lemke, G. Notch2: a second mammalian Notch gene. Development 116, 931–941 ( 1992).

    CAS  PubMed  Google Scholar 

  29. Lardelli, M., Dahlstrand, J. & Lendahl, U. The novel Notch homologue mouse Notch3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech. Dev. 46, 123–136 (1994).

    Article  CAS  Google Scholar 

  30. Lindsell, C. E., Boulter, J., diSibio, G., Gossler, A. & Weinmaster, G. Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol. Cell. Neurosci. 8, 14– 27 (1996).

    Article  CAS  Google Scholar 

  31. Bettenhausen, B., de Angelis, M. H., Simon, D., Guenet, J. L. & Gossler, A. Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development 121, 2407–2418 (1995).

    CAS  PubMed  Google Scholar 

  32. Lindsell, C. E., Shawber, C. J., Boulter, J. & Weinmaster, G. Jagged: a mammalian ligand that activates Notch1. Cell 80, 909–917 (1995).

    Article  CAS  Google Scholar 

  33. Shawber, C., Boulter, J., Lindsell, C. E. & Weinmaster, G. Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev. Biol. 180, 370–376 (1996).

    Article  CAS  Google Scholar 

  34. Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G. & Gridley, T. Notch1 is essential for postimplantation development in mice. Genes Dev. 8, 707– 719 (1994).

    Article  CAS  Google Scholar 

  35. Conlon, R. A., Reaume, A. G. & Rossant, J. Notch1 is required for the coordinate segmentation of somites. Development 121, 1533– 1545 (1995).

    CAS  PubMed  Google Scholar 

  36. Lardelli, M., Williams, R., Mitsiadis, T. & Lendahl, U. Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development. Mech. Dev. 59, 177–190 (1996).

    Article  CAS  Google Scholar 

  37. Chenn, A. & McConnell, S. K. Cleavage orientation and the asymmetric inheritance of Notch 1 immunoreactivity in mammalian neurogenesis. Cell 82, 631–641 (1995).

    Article  CAS  Google Scholar 

  38. Gonatas, J. O., Gonatas, M. K., Stieber, A. & Fleischer, B. Isolation and characterization of an enriched Golgi fraction from neurons of developing rat brains. J. Neurochem. 45, 497–507 (1985).

    Article  CAS  Google Scholar 

  39. Rebay, I., Fehon, R. G. & Artavanis-Tsakonas, S. Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell 74, 319–329 (1993).

    Article  CAS  Google Scholar 

  40. Schmechel, D. E., Brightman, M. W. & Marangos, P. J. Neurons switch from non-neuronal enolase to neuron-specific enolase during differentiation. Brain Res. 190, 195–214 (1980).

    Article  CAS  Google Scholar 

  41. Forss-Petter, S. et al. Transgenic mice expressing β-galactosidase in mature neurons under neuron-specific enolase promoter control. Neuron 5, 187–197 ( 1990).

    Article  CAS  Google Scholar 

  42. Shawber, C. et al. Notch signaling inhibits muscle cell differentiation through a CBF1–independent pathway. Development 122, 3765–3773 (1996).

    CAS  PubMed  Google Scholar 

  43. Qi, H. et al. Processing of the Notch ligand Delta by the metalloprotease Kuzbanian. Science 283, 91–94 (1999).

    Article  CAS  Google Scholar 

  44. Berezovska, O. et al. Notch1 inhibits neurite outgrowth in postmitotic primary neurons. Neuroscience 93, 433– 439 (1999).

    Article  CAS  Google Scholar 

  45. Sestan, N., Artavanis-Tsakonas, A. & Rakic, P. Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling. Science 286, 741–746 (1999).

    Article  CAS  Google Scholar 

  46. Giniger, E., Jan, L. Y. & Jan, Y.-N. Specifying the path of the intersegmental nerve of the Drosophila embryo: a role for Delta and Notch. Development 117, 431–440 ( 1993).

    CAS  PubMed  Google Scholar 

  47. Giniger, E. A role for Abl in Notch signaling. Neuron 20, 667–681 (1998).

    Article  CAS  Google Scholar 

  48. Fambrough, D., Pan, D., Rubin, G. M. & Goodman, C. S. The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila. Proc. Natl. Acad. Sci. USA 93, 13233–13238 (1996).

    Article  CAS  Google Scholar 

  49. Threadgill, R., Bobb, K. & Ghosh, A. Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19, 625–634 ( 1997).

    Article  CAS  Google Scholar 

  50. Thormodsson, F. R., Redmond, L. & Hockfield, S. Identification of nuclear proteins that are developmentally regulated in embryonic rat brain. J. Neurochem. 64, 1919–1927 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Diane Hayward for providing us with CBF1 reporter constructs, Carrie Shawber and Libby Walker for the pCDNA3.FCDN1 plasmid, Donna Nofziger for affinity purification of the 93-4 antisera, Greg Sutcliffe for the NSE-CAT construct, Yuh-Nung Jan, Weimin Zhong and Connie Cepko for discussions and members of the Ghosh lab for comments on the manuscript. This work was supported by NIH grant NS36176 and the Pew Scholars Program (A.G.).

Author information

Authors and Affiliations

  1. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21205 , Maryland, USA

    Lori Redmond, Sang-Rog Oh & Anirvan Ghosh

  2. Department of Biological Chemistry, University of California Los Angeles School of Medicine, Los Angeles, 90095, California, USA

    Carol Hicks & Gerry Weinmaster

Authors
  1. Lori Redmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang-Rog Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carol Hicks
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerry Weinmaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anirvan Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anirvan Ghosh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Redmond, L., Oh, SR., Hicks, C. et al. Nuclear Notch1 signaling and the regulation of dendritic development . Nat Neurosci 3, 30–40 (2000). https://doi.org/10.1038/71104

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/71104

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