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Biomolecules
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Notch Signalling and Cell Fate
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Notch Signalling and Cell Fate

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (1 October 2021) | Viewed by 19075

Special Issue Editor

Dr. Martin Baron

E-Mail Website
Guest Editor
Division of Molecular & Cellular Function (L5), University of Manchester, Manchester M13 9PL, UK
Interests: Notch; Drosophila; endocytosis; signalling; ubiquitin ligases; structure/function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Notch is an evolutionarily conserved cell membrane receptor that mediates a vital developmental signalling pathway. Notch activation results from its proteolytic cleavage and release of its intracellular domain. The latter translocates to the nucleus and itself becomes part of the transcription factor complex that then activates Notch target genes. Despite the apparent simplicity of the pathway, with its limited number of core components, there is a huge variety of cell fate outcomes regulated by Notch, affecting cell differentiation, proliferation and apoptosis, across a plethora of developmental contexts. These include a variety of patterning processes, such lateral inhibition, boundary formation, and binary cell fate decisions across many different tissues. Notch continues to be of vital importance in the adult organism for regulation of tissue renewal, homeostasis and repair. Understanding how this complexity arises is of considerable interest and importance because altered Notch activity is associated with an increasing number of pathological conditions, including developmental disorders and cancer. Recent work has highlighted how complexity of outcomes can arise from modulations of the duration and amplitude of the Notch signal, and by the integration and convergence of signals that impinge on the control regions of target genes. The regulatory networks that integrate different inputs and modulate the dynamics of the signal therefore have an important role to play in directing proper cell fate decisions across space and time. This Special Issue aims to shed light on the Notch regulatory mechanisms that control such cell fate decisions. Areas of interest include, but are not limited to, the specialisation of different Notch homologues, regulation of Notch signalling dynamics, analysis of Notch regulatory networks and cross talk, Notch and stem cells, Notch-regulated cell fate decisions in disease, roles of chromatin modifications, and the contributions of mathematical modelling to the study of Notch regulatory networks.

We look forward to receiving and reading your contributions in the form of either original research or topical reviews.

Dr. Martin Baron
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Notch
  • cell fate
  • developmental pattering
  • stem cells
  • computational modelling
  • signal dynamics
  • signalling networks and cross talk
  • Notch and disease

Published Papers (6 papers)

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Research

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16 pages, 8430 KiB  
Article
Notch Missense Mutations in Drosophila Reveal Functions of Specific EGF-like Repeats in Notch Folding, Trafficking, and Signaling
by Hilman Nurmahdi, Mao Hasegawa, Elzava Yuslimatin Mujizah, Takeshi Sasamura, Mikiko Inaki, Shinya Yamamoto, Tomoko Yamakawa and Kenji Matsuno
Biomolecules 2022, 12(12), 1752; https://doi.org/10.3390/biom12121752 - 25 Nov 2022
Cited by 3 | Viewed by 1458
Abstract
Notch signaling plays various roles in cell-fate specification through direct cell–cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific [...] Read more.
Notch signaling plays various roles in cell-fate specification through direct cell–cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific functions of most remain unclear. To investigate the role of each EGF-like repeat, we used 19 previously identified missense mutations of Notch with unique amino acid substitutions in various EGF-like repeats and a transmembrane domain; 17 of these were identified through a single genetic screen. We assessed these mutants’ phenotypes in the nervous system and hindgut during embryogenesis, and found that 10 of the 19 Notch mutants had defects in both lateral inhibition and inductive Notch signaling, showing context dependency. Of these 10 mutants, six accumulated Notch in the endoplasmic reticulum (ER), and these six were located in EGF-like repeats 8–10 or 25. Mutations with cysteine substitutions were not always coupled with ER accumulation. This suggests that certain EGF-like repeats may be particularly susceptible to structural perturbation, resulting in a misfolded and inactive Notch product that accumulates in the ER. Thus, we propose that these EGF-like repeats may be integral to Notch folding. Full article
(This article belongs to the Special Issue Notch Signalling and Cell Fate)
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20 pages, 7047 KiB  
Article
The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in Drosophila melanogaster
by Anja C. Nagel, Dominik Müller, Mirjam Zimmermann and Anette Preiss
Biomolecules 2021, 11(11), 1672; https://doi.org/10.3390/biom11111672 - 10 Nov 2021
Cited by 1 | Viewed by 2373
Abstract
The Notch signaling pathway is pivotal to cellular differentiation. Activation of this pathway involves proteolysis of the Notch receptor and the release of the biologically active Notch intracellular domain, acting as a transcriptional co-activator of Notch target genes. While the regulation of Notch [...] Read more.
The Notch signaling pathway is pivotal to cellular differentiation. Activation of this pathway involves proteolysis of the Notch receptor and the release of the biologically active Notch intracellular domain, acting as a transcriptional co-activator of Notch target genes. While the regulation of Notch signaling dynamics at the level of ligand–receptor interaction, endocytosis, and transcriptional regulation has been well studied, little is known about factors influencing Notch cleavage. We identified EP555 as a suppressor of the Notch antagonist Hairless (H). EP555 drives expression of CG32521 encoding membrane-bound proteins, which we accordingly rename membrane-bound Notch regulator (mnr). Within the signal-receiving cell, upregulation of Mnr stimulates Notch receptor activation, whereas a knockdown reduces it, without apparent influence on ligand–receptor interaction. We provide evidence that Mnr plays a role in γ-secretase-mediated intramembrane cleavage of the Notch receptor. As revealed by a fly-eye-based reporter system, γ-secretase activity is stimulated by the overexpression of Mnr, and is inhibited by its knockdown. We conclude that Mnr proteins support Notch signaling activity by fostering the cleavage of the Notch receptor. With Mnr, we identified a membrane-bound factor directly augmenting Notch intra-membrane processing, thereby acting as a positive regulator of Notch signaling activity. Full article
(This article belongs to the Special Issue Notch Signalling and Cell Fate)
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14 pages, 1556 KiB  
Article
Auto-Regulation of Transcription and Translation: Oscillations, Excitability and Intermittency
by Philip J. Murray, Eleonore Ocana, Hedda A. Meijer and Jacqueline Kim Dale
Biomolecules 2021, 11(11), 1566; https://doi.org/10.3390/biom11111566 - 22 Oct 2021
Cited by 2 | Viewed by 1929
Abstract
Several members of the Hes/Her family, conserved targets of the Notch signalling pathway, encode transcriptional repressors that dimerise, bind DNA and self-repress. Such autoinhibition of transcription can yield homeostasis and, in the presence of delays that account for processes such as transcription, splicing [...] Read more.
Several members of the Hes/Her family, conserved targets of the Notch signalling pathway, encode transcriptional repressors that dimerise, bind DNA and self-repress. Such autoinhibition of transcription can yield homeostasis and, in the presence of delays that account for processes such as transcription, splicing and transport, oscillations. Whilst previous models of autoinhibition of transcription have tended to treat processes such as translation as being unregulated (and hence linear), here we develop and explore a mathematical model that considers autoinhibition of transcription together with nonlinear regulation of translation. It is demonstrated that such a model can yield, in the absence of delays, nonlinear dynamical behaviours such as excitability, homeostasis, oscillations and intermittency. These results indicate that regulation of translation as well as transcription allows for a much richer range of behaviours than is possible with autoregulation of transcription alone. A number of experiments are suggested that would that allow for the signature of autoregulation of translation as well as transcription to be experimentally detected in a Notch signalling system. Full article
(This article belongs to the Special Issue Notch Signalling and Cell Fate)
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Review

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20 pages, 2063 KiB  
Review
E3 Ubiquitin Ligase Regulators of Notch Receptor Endocytosis: From Flies to Humans
by Raluca Revici, Samira Hosseini-Alghaderi, Fabienne Haslam, Rory Whiteford and Martin Baron
Biomolecules 2022, 12(2), 224; https://doi.org/10.3390/biom12020224 - 27 Jan 2022
Cited by 3 | Viewed by 3731
Abstract
Notch is a developmental receptor, conserved in the evolution of the metazoa, which regulates cell fate proliferation and survival in numerous developmental contexts, and also regulates tissue renewal and repair in adult organisms. Notch is activated by proteolytic removal of its extracellular domain [...] Read more.
Notch is a developmental receptor, conserved in the evolution of the metazoa, which regulates cell fate proliferation and survival in numerous developmental contexts, and also regulates tissue renewal and repair in adult organisms. Notch is activated by proteolytic removal of its extracellular domain and the subsequent release of its intracellular domain, which then acts in the nucleus as part of a transcription factor complex. Numerous regulatory mechanisms exist to tune the amplitude, duration and spatial patterning of this core signalling mechanism. In Drosophila, Deltex (Dx) and Suppressor of dx (Su(dx)) are E3 ubiquitin ligases which interact with the Notch intracellular domain to regulate its endocytic trafficking, with impacts on both ligand-dependent and ligand-independent signal activation. Homologues of Dx and Su(dx) have been shown to also interact with one or more of the four mammalian Notch proteins and other target substrates. Studies have shown similarities, specialisations and diversifications of the roles of these Notch regulators. This review collates together current research on vertebrate Dx and Su(dx)-related proteins, provides an overview of their various roles, and discusses their contributions to cell fate regulation and disease. Full article
(This article belongs to the Special Issue Notch Signalling and Cell Fate)
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23 pages, 2274 KiB  
Review
The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation
by Judith Hounjet and Marc Vooijs
Biomolecules 2021, 11(9), 1369; https://doi.org/10.3390/biom11091369 - 16 Sep 2021
Cited by 12 | Viewed by 4004
Abstract
Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities [...] Read more.
Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting. Full article
(This article belongs to the Special Issue Notch Signalling and Cell Fate)
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19 pages, 2077 KiB  
Review
To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis
by Han Leng Ng, Elizabeth Quail, Mark N. Cruickshank and Daniela Ulgiati
Biomolecules 2021, 11(6), 849; https://doi.org/10.3390/biom11060849 - 07 Jun 2021
Cited by 6 | Viewed by 4036
Abstract
Notch signaling forms an evolutionarily conserved juxtacrine pathway crucial for cellular development. Initially identified in Drosophila wing morphogenesis, Notch signaling has since been demonstrated to play pivotal roles in governing mammalian cellular development in a large variety of cell types. Indeed, abolishing Notch [...] Read more.
Notch signaling forms an evolutionarily conserved juxtacrine pathway crucial for cellular development. Initially identified in Drosophila wing morphogenesis, Notch signaling has since been demonstrated to play pivotal roles in governing mammalian cellular development in a large variety of cell types. Indeed, abolishing Notch constituents in mouse models result in embryonic lethality, demonstrating that Notch signaling is critical for development and differentiation. In this review, we focus on the crucial role of Notch signaling in governing embryogenesis and differentiation of multiple progenitor cell types. Using hematopoiesis as a diverse cellular model, we highlight the role of Notch in regulating the cell fate of common lymphoid progenitors. Additionally, the influence of Notch through microenvironment interplay with lymphoid cells and how dysregulation influences disease processes is explored. Furthermore, bi-directional and lateral Notch signaling between ligand expressing source cells and target cells are investigated, indicating potentially novel therapeutic options for treatment of Notch-mediated diseases. Finally, we discuss the role of cis-inhibition in regulating Notch signaling in mammalian development. Full article
(This article belongs to the Special Issue Notch Signalling and Cell Fate)
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