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Notch signalling in context

Nature Reviews Molecular Cell Biology volume 17, pages 722–735 (2016)Cite this article

Subjects

Key Points

  • The highly conserved Notch cell–cell signalling pathway operates in many different contexts across which the consequences can differ widely, despite the fact that the core pathway is very simple.

  • Many different types of regulation contribute to the differing outcomes of Notch signalling, ranging from tissue-level coordination to nuclear governance.

  • The pattern of expression of the ligands (which are transmembrane proteins), receptors and crucial modifying enzymes is one level of regulation that is common to many signalling pathways. However, the one-to-one interaction between ligand and receptor in Notch signalling places extra emphasis on this type of regulation, especially because the ligand and receptor can cis-inhibit one another when present in the same cells.

  • 'Topological' tissue organization and the extent of cell–cell contacts are likely to be of unusual importance in influencing the levels of Notch activation because the ligands are transmembrane proteins.

  • Nuclear context, in the form of cell-type-specific transcription factors and chromatin organization, is a primary level of control in generating qualitatively different outcomes after Notch activation. In addition, the wiring of the gene regulatory networks in the signal-receiving cells contributes to the diversity of responses and to the nature of its crosstalk with other signalling pathways.

  • Together, these regulatory mechanisms make the Notch pathway versatile and able to undertake many different roles. But they are also susceptible to perturbations, and may be a contributory factor in Notch-related diseases.

Abstract

The highly conserved Notch signalling pathway functions in many different developmental and homeostatic processes, which raises the question of how this pathway can achieve such diverse outcomes. With a direct route from the membrane to the nucleus, the Notch pathway has fewer opportunities for regulation than do many other signalling pathways, yet it generates exquisitely patterned structures, including sensory hair cells and branched arterial networks. More confusingly, its activity promotes tissue growth and cancers in some circumstances but cell death and tumour suppression in others. Many different regulatory mechanisms help to shape the activity of the Notch pathway, generating functional outputs that are appropriate for each context. These mechanisms include the receptor–ligand landscape, the tissue topology, the nuclear environment and the connectivity of the regulatory networks.

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Figure 1: Ligand binding leads to exposure of the cleavage site in Notch.
Figure 2: The consequences of cis inhibition and Fringe expression on Notch signalling.
Figure 3: Influence of cell contacts and tissue architecture on signalling.
Figure 4: Regulation of the nuclear context.
Figure 5: Transitions in Notch-responsive programmes.

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Acknowledgements

The author apologizes for the many articles that could not be cited owing to space limitations. She also thanks M. Gomez-Lamarca for help in preparing the figures and A. Asselin for the drawings in Figure 3. Work in the Bray laboratory is supported by a programme grant from the UK Medical Research Council as well as by funding from the UK Biology and Biotechnology Research Council.

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  1. Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK

    Sarah J. Bray

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Glossary

Paralogues

Sequences, or genes, that have originated from a common ancestral sequence, or gene, by a duplication event.

Lateral inhibition

The process by which a cell with a particular fate interacts with its immediate neighbours to prevent them from adopting the same fate.

Growth organizer

Group of cells that produces signals necessary to promote growth of a tissue.

Somitogenesis

The process by which somites, blocks of mesoderm that give rise to axial muscles, bones and dermis in vertebrates, are formed.

Somite clock

Oscillatory mechanism that ensures periodic formation of somites.

Placode

Ectodermal thickening from which a sense organ or ganglion develops.

Tip cells

Leading cells of sprouting blood vessels that sense their environment for guidance cues.

Sprouting

Initiation of a branch from blood vessels during angiogenesis

Haemangiogenic endothelium

A subset of endothelial cells that can give rise to haematopoietic stem cells as well as to blood vessels.

EGF repeats

Protein domains, commonly found in the extracellular domain of membrane-bound proteins, that are related to a sequence in EGF and include cysteine residues involved in disulfide bonds. EGF-like domains frequently occur in numerous tandem copies in proteins, as in Notch.

SOP cells

(Sensory organ precursor cells). Cells that give rise to all of the cells in a Drosophila species sensory organ.

Endosomal sorting complex required for transport

(ESCRT). The multiprotein ESCRT machinery (ESCRT-I, -II and -III) promotes inward vesiculation at the limiting membrane of the sorting endosome, and selects cargo proteins for delivery to the intra-luminal vesicles of multivesicular bodies.

Filopodia

Thin cellular processes containing long, unbranched, parallel bundles of actin filaments.

Adherens junctions

Actin-filament-associated, epithelial cell–cell junctions that have classical cadherins as their core component.

End feet

The name given to the apical membrane surface as a consequence of cortical neuroepithelial progenitors becoming very tall and thin over the course of development.

Notum

Structure that is part of the back of an animal; in insects, the back of the thorax.

Xanthophores

Yellow chromatophores, pigment-containing and light-reflecting cells, of a fish, amphibian or reptile.

Melanophores

Melanin-containing cells of a fish, amphibian or reptile that appear black or dark-brown because of melanin's light-absorbing qualities.

Pioneer factor

A subset of transcription factors that are capable of binding to their target-motifs even when located in DNA that is wrapped around nucleosomes, enabling them to initiate changes in regulation at silent enhancers.

Enhancers

DNA segments that increase transcription of a linked promoter if placed in either orientation, upstream or downstream.

HES family

A family of genes related to Hairy and Enhancer of split that encode basic helix–loop–helix nuclear proteins that suppress transcription.

Basic helix–loop–helix

(bHLH). A basic domain adjacent to two α-helices separated by a loop (the HLH domain), which binds DNA in a sequence-specific manner.

GATA transcription factors

A family of transcription factors that contain a zinc-finger motif that was first identified in the vertebrate GATA1 protein. These transcription factors bind the consensus sequence GATA in the regulatory regions of genes.

Zinc finger

A motif in proteins that contains conserved cysteine residues. The sulfydryl groups of the cysteines coordinate a Zn2+ ion.

BEN-SOLO proteins

Proteins containing only a BEN domain, a sequence-specific DNA-binding domain that has been identified in some transcription repressors.

Neurogenic transition

Change in the competence of neural precursor cells that enable them to generate different types of neural or glial progeny.

Mediator complex

A multiprotein complex that is required for gene transcription by RNA polymerase II.

Homologous to E6-AP carboxyl terminus

(HECT). The HECT domain is an ∼350-amino-acid domain that is highly conserved among a family of E3 enzymes.

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Bray, S. Notch signalling in context. Nat Rev Mol Cell Biol 17, 722–735 (2016). https://doi.org/10.1038/nrm.2016.94

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