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The Notch signalling system: recent insights into the complexity of a conserved pathway

Nature Reviews Genetics volume 13, pages 654–666 (2012)Cite this article

Subjects

Key Points

  • The highly pleiotropic Notch signalling pathway functions to control cell-fate determination in nearly every tissue and organ by influencing differentiation, proliferation or apoptotic events.

  • Notch pathway activity is highly dosage-sensitive and is regulated at different points along the signal transduction pathway by multiple mechanisms, including transcriptional control, endosomal trafficking and various post-translational modifications and microRNAs.

  • The developmental action of Notch links the fate of one cell to that of its immediate cellular neighbour, and recent genome-scale studies in Drosophila melanogaster indicate a complex network of hundreds of genes can affect Notch activity.

  • Multiple independent genome-wide screens in different developmental contexts in D. melanogaster indicate that a large proportion of the D. melanogaster genome is capable of affecting or modulating Notch activity and, by extension, other signalling pathways.

  • Positioning the vast number of genetic modifiers onto a single-protein complex map allows these genes to be connected into one unified network that provides a potential functional framework for modifying proteins in the context of all protein interactions within a cell, thereby generating numerous testable hypotheses.

Abstract

Notch signalling links the fate of one cell to that of an immediate neighbour and consequently controls differentiation, proliferation and apoptotic events in multiple metazoan tissues. Perturbations in this pathway activity have been linked to several human genetic disorders and cancers. Recent genome-scale studies in Drosophila melanogaster have revealed an extraordinarily complex network of genes that can affect Notch activity. This highly interconnected network contrasts our traditional view of the Notch pathway as a simple linear sequence of events. Although we now have an unprecedented insight into the way in which such a fundamental signalling mechanism is controlled by the genome, we are faced with serious challenges in analysing the underlying molecular mechanisms of Notch signal control.

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Figure 1: Summary of the main features of Notch signalling.
Figure 2: Overlap of Notch genetic modifiers from different genome-wide screens in Drosophila melanogaster.
Figure 3: Summary of crosstalk between Notch and other signalling pathways.
Figure 4: Mapping genetic modifiers on proteome map.

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Acknowledgements

We would like to thank A. Louvi, D. Dimlich, K. Hori, B. Obar and A. Sen for critically reading the manuscript. Special thanks to J. Iwasa for the Notch pathway animations. We also apologize to our colleagues whose original work was not discussed or cited here in the interest of space. Work in the Artavanis-Tsakonas laboratory is supported by grants from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    K. G. Guruharsha, Mark W. Kankel & Spyros Artavanis-Tsakonas

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  1. K. G. Guruharsha
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  2. Mark W. Kankel
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Correspondence to Spyros Artavanis-Tsakonas.

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Supplementary information

Supplementary information S1 (movie)

(MOV 5028 kb)

Supplementary information S2 (movie)

(MOV 1289 kb)

Supplementary information S3 (movie)

(MOV 3803 kb)

Supplementary information S4 (table)

(XLS 308 kb)

Supplementary information S5 (figure)

High-resolution image file from Figure 4: Mapping genetic modifiers on proteome map (PDF 7288 kb)

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FURTHER INFORMATION

Spyros Artavanis-Tsakonas's homepage

BioGRID

Drosophila Protein Interaction Map

DroID

Exelixis

Fly Stocks of National Institute of Genetics (NIG-FLY)

Proteomics Identifications database (PRIDE)

MINT

modEncode

Pathguide

Reactome

Vienna Drosophila RNAi Center (VDRC)

Glossary

Haploinsufficiency

A genetic condition in a diploid organism in which a single functional copy of a gene fails to generate sufficient gene product, leading to an abnormal or diseased state.

Triplomutant

A genetic variant that carries three copies of a single gene, as opposed to the normal two copies, and displays a specific mutant phenotype that may include lethality or morphological defects. This mutant is distinct from aneuploidy, which alters copy numbers for large numbers of genes owing to chromosomal aberrations.

Alagille's syndrome

An inherited autosomal dominant genetic disorder that can affect multiple vital organs, such as the liver, heart and other body parts. The disorder may also affect the blood vessels within the brain, spinal cord and the kidneys. The estimated prevalence of Alagille's syndrome is 1 in 70,000 newborns.

Transcriptional feedback

A regulatory loop in which the gene products positively or negatively regulate the expression or activity of other members of the same pathway and therefore regulate themselves.

Equivalence group

A group of unspecified cells that have the same developmental potential to adopt various fates. Typically, these are cells from an equivalence group that receive a signal take on fates that are distinct from those cells that do not receive a signal and therefore adopt a default fate.

Quantitative proteomics

Quantitative proteomics is identical to general (qualitative) proteomics but includes quantification as an additional dimension. Information about differences between two or more protein samples is obtained with the use of isotopes or mass tags that are distinguishable in mass spectrometry.

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Guruharsha, K., Kankel, M. & Artavanis-Tsakonas, S. The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 13, 654–666 (2012). https://doi.org/10.1038/nrg3272

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