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  • Review Article
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Not(ch) just development: Notch signalling in the adult brain

Nature Reviews Neuroscience volume 12, pages 269–283 (2011)Cite this article

Subjects

Key Points

  • Notch is an evolutionarily conserved, membrane-bound receptor whose ligands are also membrane-bound. As ligand-mediated enzymatic cleavage of Notch results in nuclear signalling through canonical and non-canonical pathways, Notch is considered a key integrator of environmental signals and can be thought of as a 'membrane-bound transcription factor'.

  • The Notch signalling cascade is well known for its role during CNS development. However, technical advancements in gene and protein manipulation strategies have revealed both conserved and novel roles for Notch signalling in the adult brain in processes as diverse as neural stem cell maintenance, the regulation of neuronal plasticity and even survival.

  • In neural stem cells, Notch regulates the cell cycle to balance stem cell maintenance with production of daughter cells. The ability of Notch to regulate proliferation is highly cell-type dependent, with more neuronally committed progeny responsive to a variety of environmental cues, not just Notch ligands.

  • Notch signalling also regulates neuronal migration, in part through reelin–DAB (disabled homologue) signalling. Additional research suggests that Notch-mediated regulation of migration may also rely on indirect regulation of microtubule stability.

  • Neuronal dendritic plasticity in the adult brain is reliant on Notch signalling, but is notably age- and 'cell stage'-dependent. For example, Notch signalling regulates dendritic arborization in nascent neurons, but may only fine-tune dendritic spines in 'older' neurons.

  • Notch signalling regulates synaptic plasticity and behaviour, but the direction of this regulation is exquisitely dose- and context-dependent.

  • In healthy, non-aged animals, the regulation of neuron survival by Notch signalling is difficult to separate from its effects on dendritic arborization and spine maintenance. However, in models of neurodegenerative disease, Notch signalling seems to drive dendritic atrophy and may lead to neuron death.

  • Increasing evidence indicates that activity-induced Notch signalling in neurons has an important role in cellular forms of memory and behavioural demonstration of memory.

  • Disruptions in Notch signalling result in diseases that have a strong neurodegenerative component. Therefore, comprehension of Notch signalling in the adult — and fully understanding how it is similar to or different from that in the developing animal — has substantial therapeutic implications.

  • Despite advances in our knowledge of the influence of Notch signalling on a wide range of cell types, stages and functions, it remains challenging to predict the outcome of activation. It is crucial to consider dose-, context- and age-dependence, and to consider the crosstalk with other signalling pathways (which are likely to be as dynamic as the Notch pathway).

Abstract

The Notch pathway is often regarded as a developmental pathway, but components of Notch signalling are expressed and active in the adult brain. With the advent of more sophisticated genetic manipulations, evidence has emerged that suggests both conserved and novel roles for Notch signalling in the adult brain. Not surprisingly, Notch is a key regulator of adult neural stem cells, but it is increasingly clear that Notch signalling also has roles in the regulation of migration, morphology, synaptic plasticity and survival of immature and mature neurons. Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway.

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Figure 1: Notch signal transduction.
Figure 2: Pleiotropic roles for Notch signalling in the adult brain.
Figure 3: Notch integrates signals to coordinate a context-specific response.

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Acknowledgements

J.L.A. would like to thank the Medical Science Training Program (MSTP) at both the University of Texas Southwestern Medical Centre, at Dallas, Texas, USA, and Mount Sinai School of Medicine, New York, New York, USA, as well as the US National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA) for their support. J.J.B. was supported by the Connecticut Stem Cell Research Grant Program during the preparation of this manuscript and is currently supported by the Cedars-Sinai Regenerative Medicine Institute, Los Angeles, California, USA. A.J.E. is supported by grants from the US National Institutes of Health (NIH), including grants from NIDA (DA016765, DA016765-07S, DA023555) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK079328), the National Alliance for Research on Schizophrenia and Depression, the National Aeronautics and Space Administration, and the Norwegian Department of Public Health. P.R. is supported by grants from the US National Institute of Neurological Disorders and Stroke (NINDS), NIDA and the Kavli Institute of Neuroscience at Yale University School of Medicine, New Haven, Connecticut, USA.

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  1. Jessica L. Ables and Joshua J. Breunig: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Jessica L. Ables & Amelia J. Eisch

  2. Department of Biomedical Sciences, and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Joshua J. Breunig

  3. Department of Neurobiology, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Joshua J. Breunig & Pasko Rakic

  4. Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Joshua J. Breunig & Pasko Rakic

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Ables, J., Breunig, J., Eisch, A. et al. Not(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci 12, 269–283 (2011). https://doi.org/10.1038/nrn3024

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