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  • Review Article
  • Published:

Notch signalling in vertebrate neural development

Nature Reviews Neuroscience volume 7, pages 93–102 (2006)Cite this article

Key Points

  • The Notch signalling pathway is one of the few fundamental signalling pathways that govern metazoan development. Notch signals couple cell fate acquisition by an individual cell to the cell fate choices made by its neighbours.

  • The Notch cell-surface receptor defines the central element of this signalling mechanism, and its interaction with the membrane-bound ligands delta or serrate (jagged) expressed in adjacent cells triggers a series of proteolytic events that eventually release the intracellular domain, which, on translocation into the nucleus, guides downstream gene activity.

  • Notch controls cell fate in a context-dependent manner, and a large number of Notch signal modifiers have been identified, defining a complex and intriguing Notch-related genetic circuitry.

  • The outcome of Notch pathway activation depends on how Notch signals integrate their action with other cellular signals and factors in a given cellular environment to affect differentiation, proliferation and apoptotic events.

  • Notch signals have a pleiotropic action in the nervous system, but have been broadly shown to inhibit neuronal differentiation.

  • Notch signals have also been implicated in promoting the differentiation of most glial subtypes, with the exception of oligodendrocytes.

  • Notch signals affect differentiated neurons, and intracellular Notch — although generally undetectable in the nucleus of most cells — can be clearly seen in the nucleus of postmitotic neurons. Modulation of Notch signalling in postmitotic neurons affects the morphology of neurites.

  • Targeted mutations in Notch pathway elements reveal the broad spectrum of processes and tissues that can be affected by Notch, and, in humans, mutations in Notch pathway elements are associated with several disorders.

  • Many molecular aspects of Notch signalling await elucidation, and the mapping of the complex genetic circuitry that is capable of controlling Notch signals remains to be defined. Most importantly, we have no real understanding of how Notch integrates its actions with other cellular signals to control specific developmental events.

Abstract

Signals through the Notch receptors are used throughout development to control cellular fate choices. Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells. As we review here, Notch signalling affects the development of the nervous system at many different levels. Understanding the complex genetic circuitry that allows Notch signals to affect specific cell fates in a context-specific manner defines the next challenge, especially as such an understanding might have important implications for regenerative medicine.

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Figure 1: Drosophila melanogaster embryos stained with an antibody against horseradish peroxidase that recognizes neural tissue.
Figure 2: The core of the Notch signalling pathway.
Figure 3: A schematic summarizing the effects of Notch signal activation on cell fate decisions in the vertebrate nervous system.

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Acknowledgements

We thank our lab colleagues G. Hurlbut, J. Arboleda-Velasquez and A. Veraksa for comments. Special thanks to D. van Vactor and N. Gaiano for their insightful discussions. We were supported by the National Institutes of Health (NIH), USA.

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Authors and Affiliations

  1. Department of Neurosurgery, Yale University School of Medicine, P.O. Box 208082, New Haven, 06520-8082, Connecticut, USA

    Angeliki Louvi

  2. Department of Cell Biology, Harvard Medical School and MGH Cancer Center, Building 149, 13th Street, Charlestown, 02129, Massachusetts, USA

    Spyros Artavanis-Tsakonas

  3. Collège de France, 11, place Marcelin Berthelot, Paris, 75231, Cedex 05, France

    Spyros Artavanis-Tsakonas

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  1. Angeliki Louvi
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Correspondence to Spyros Artavanis-Tsakonas.

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Glossary

Chromosomal walk

A procedure pioneered in David Hogness's laboratory that allows the isolation of overlapping genomic fragments from a genomic phage library.

Paralogues

Two or more genes at distinct chromosomal locations in the same organism that have structural and functional similarities indicating that they derive from a common ancestral gene.

Müller glia

The main glial cell type in the retina.

Ganglion cells

The projection neurons of the retina and the first cells produced during retinal development.

Neurospheres

The multicellular floating clonal derivatives of the neural stem cells placed in culture.

CADASIL

(Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). An inherited small vessel disease that leads to strokes and vascular cognitive impairment.

Dysproliferative

Indicates abnormal cell proliferation events and derives from the word proliferation and the Greek prefix 'dys', akin to the English 'mis'.

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Louvi, A., Artavanis-Tsakonas, S. Notch signalling in vertebrate neural development. Nat Rev Neurosci 7, 93–102 (2006). https://doi.org/10.1038/nrn1847

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