Syndromes and Diseases Associated with the Notch Signalling Pathway


The Notch signalling pathway refers to a highly conserved complex cell interaction mechanism, playing a crucial role in metazoan development, which eventually dictates cell fates through the implementation of differentiation, proliferation and apoptosis, ultimately influencing organ formation and morphogenesis by unlocking specific developmental programmes. In mammals, the regulation of neurogenesis, myogenesis, angiogenesis, haematopoiesis and epithelial–mesenchymal transition are all crucially influenced by Notch signalling and to date 10 genes, either core components of the pathway or signalling targets, are implicated in a diverse group of human Mendelian diseases/syndromes when mutated in the germline. These can be broadly grouped into those conditions dominated by axial skeletal defects – the spondylocostal dysostoses; those with predominantly vascular or cardiovascular abnormalities – Alagille syndrome, NOTCH1‐related congenital cardiac anomalies and CADASIL; Hajdu–Cheney syndrome, a multisystem disorder dominated by skeletal anomalies, and neurological degeneration – Alzheimer disease type 3. Notch signalling is also widely implicated in somatic genomic mutational events leading to cancer and malignancy, the best known example of which is T‐cell acute lymphoblastic leukaemia.

Key Concepts:

  • Notch signalling is a highly conserved pathway in metazoan development.

  • The Notch gene family encodes cell surface transmembrane receptors which mediate cellular functions through direct cell–cell contact.

  • The activation of membrane‐bound Notch results in proteolytic cleavage Notch intracellular domain (NICD), which translocates to the nucleus.

  • The Notch intracellular domain (NICD) converts downstream targets from transcriptional repressors to transcriptional activators.

  • Notch signalling determines cell fates in neurogenesis, myogenesis, angiogenesis, haematopoiesis and epithelial–mesenchymal transition.

  • A key role of the Notch signalling pathway is in the developmental integrity of somitogenesis.

  • Syndromes caused by germline mutations in Notch pathway genes include spondylocostal dysostosis, Alagille and Hajdu–Cheney.

  • Syndromes with predominantly (cardio)vascular effects due to mutations in Notch pathway genes include congenital heart disease and CADASIL.

  • A form of familial presenile dementia (Alzheimer disease type 3) is due to mutated PSEN1, a Notch pathway gene.

  • Somatic mutations in certain Notch pathway genes are increasingly being shown to contribute to various cancerous conditions.

Keywords: Notch signalling; spondylocostal dysostosis; spondylothoracic dysostosis; Alagille syndrome; Hajdu–Cheney syndrome; CADASIL; DLL3; MESP2; LFNG; HES7; TBX6; NOTCH1; NOTCH2; NOTCH3; PSEN1

Figure 1.

Notch signalling from the cell membrane to the nucleus. (a) Ligands of the Jagged (JAG1 and JAG2) and Delta‐like (DLL1, DLL3 and DLL4) families (upper cell, shown in green) interact with Notch family transmembrane receptors (NOTCH1–NOTCH4) on an adjacent cell. (b) Receptor–ligand interactions result in the cleavage of the Notch receptor, mediated by Presenilin, and release of the NICD to the cytoplasm. (c) The NICD translocates to the nucleus. NICD forms a complex with the RBPSUH protein, displacing histone deacetylase and corepressor complexes, leading to the transcriptional activation of Notch target genes, including Hes and Hey.

Figure 2.

Somitogenesis: the segmentation clock oscillator and determination front. The oscillatory ‘clock mechanism’ refers to the cyclical gene expression that behaves like a ‘Mexican wave’ that migrates along the PSM in a caudal‐rostral direction until it meets the determination front, a level that is presumably characterised by a signalling threshold at which cells become competent to respond to the segmentation clock signal, which is conceptually similar to the wavefront of the original model proposed by Cooke and Zeeman (see Further Reading). The clock signal is poorly characterised but is believed to involve three signalling pathways: FGF, Wnt and Notch (see Figure ). The wave of cyclic gene expression controlled by the segmentation clock oscillator is shown in orange on the left side of the embryos. When competent cells that pass through the determination front receive the clock signal, they simultaneously activate Mesp2 (shown in black), thereby defining the future segmental domain as shown on the right side of the embryos. During the next cycle Mesp2 expression becomes restricted to the anterior compartment of S–I (grey). The role of retinoic acid remains debated. (T – time in segmentation clock cycle unit.) Reproduced from Dequéant and Pourquié (). © Nature Publishing Group.

Figure 3.

The mammalian Notch receptors and ligands involved in human mendelian disease. The schematic highlights the similarities in structure shared by the Notch receptors 1–4 on the one hand, and the DSL ligands on the other (DLL3 and JAGGED1). They are type I transmembrane proteins with their C‐terminus in the cytosol. Notch receptors have between 29 and 36 EGF‐like repeats, which are required for ligand binding. The LIN12/Notch repeats (LNR) prevent ligand‐independent signalling. C‐terminal to the transmembrane domain the receptors have an RBPj associated molecule (RAM) domain that binds RBPj/CSL, and six ankyrin repeats which moderate protein interactions. There is a nuclear localisation sequence (NLS) in the RAM domain and Notch1–3 have a second NLS. There is a transcription activation domain (TAD), and a C‐terminal polypeptide enriched in proline, glutamine, serine and threonine residues (PEST) required for the ubiquitinylation and degradation of the NICD. A TAD has not been identified in Notch3 or Notch4. DLS ligands (not DLL3) have a DLS domain and EGF‐like repeats that interact with the EGF‐like repeats of Notch. JAGGED1 has a von Willebrand factor type C domain involved in multiprotein complexes. C‐terminal to the transmembrane domain the proteins are unstructured, and Jagged1 has a PDZ ligand‐binding domain at the C‐terminus. (M – cell membrane.) Reproduced from Dunwoodie (). © Elsevier.

Figure 4.

Interaction of the Notch, Wnt and FGF pathways. Crosstalk and integration of the three distinct oscillators that function in the mouse PSM, detailing cyclic genes of the Notch, Fgf and Wnt pathways. A large number of the cyclic genes are involved in negative feedback loops. Reproduced from Gibb et al. (). © Elsevier.

Figure 5.

The radiological phenotype of SCD1 due to mutated DLL3. All vertebrae are abnormally formed to a greater or lesser extent. The smooth, ovoid appearance of many vertebrae in early childhood is referred to as the ‘pebble beach’ sign. The ribs are irregularly aligned with points of fusion. Reproduced from Turnpenny et al. (). © University of Washington.

Figure 6.

A young baby with SCD1. The neck appears short, the trunk shortened and the abdomen correspondingly protruberant because the spine is short due to generalised segmentation anomalies. Reproduced with permission from Peter D Turnpenny.

Figure 7.

The radiological phenotype of SCD2 due to mutated MESP2. All vertebrae are affected, with more angular features compared to SCD1, and the ribs (not well seen in this image) are relatively spared. Reproduced from Turnpenny et al. (). © Unversity of Washington.

Figure 8.

The radiological phenotype of severe binding domais (STD). The ribs are fused posteriorly and fan out laterally, giving a ‘crab‐like’ appearance without points of fusion along their length. In foetal life and early childhood the vertebral pedicles are more clearly visible (compared to the early appearance of SCD1), sometimes referred to as the ‘tramline’ sign.

Figure 9.

The radiological phenotype of SCD3 due to mutated LFNG. All vertebrae are abnormally segmented and the trunk severely shortened. Reproduced from Sparrow et al. (). © Elsevier.

Figure 10.

The radiological phenotype of SCD4 due to mutated HES7. G‐SDV occurs in a pattern similar to mild STD with the ribs showing fusion posteriorly and fanning out in a crab‐like fashion. Reproduced with permission from Sparrow et al. (). © Oxford University Press.

Figure 11.

The radiological phenotype of SCD5 due to mutated TBX6. This is the only Notch pathway gene identified so far that gives rise to ADSCD. Abnormal vertebral segmentation is generalised and resembles SCD1. Reproduced courtesy of Dr. Zoran Gucev.

Figure 12.

The facial phenotype of ALGS. (a) A child with deep‐set eyes, a broad nasal root and prominent chin. The palpebral fissures are not upslanting, and hypertelorism is not a feature. Reproduced from Turnpenny and Ellard (). © Nature Publishing Group. (b) A child without deep‐set eyes, though the palpebral fissures are upslanting and narrow, and there appears to be mild hypertelorism. Reproduced from Turnpenny and Ellard (). © Elsevier.



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Further Reading

Cooke J and Zeeman EC (1976) A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. Journal of Theoretical Biology 58: 455–476.

Delaune EA, François P, Shih NP and Amacher SL (2012) Single‐cell‐resolution imaging of the impact of Notch signaling and mitosis on segmentation clock dynamics. Developmental Cell 23(5): 995–1005

Hofmann M, Schuster‐Gossler K, Watabe‐Rudolph M et al. (2004) WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos. Genes & Development 18(22): 2712–2717.

Offiah A, Alman B, Cornier AS et al. (2010) Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae. American Journal of Medical Genetics 152A: 1357–1371.

Pourquié O (2011) Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell 145(5): 650–663.

Sparrow DB, Chapman G, Smith AJ et al. (2012) A mechanism for gene‐environment interaction in the etiology of congenital scoliosis. Cell 149(2): 295–306.

Turnpenny PD, Alman B, Cornier AS et al. (2007) Abnormal vertebral segmentation and the Notch signalling pathway in man. Developmental Dynamics 236: 1456–1474.

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Turnpenny, Peter D(Aug 2014) Syndromes and Diseases Associated with the Notch Signalling Pathway. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024870]