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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 829-835

Notch signaling in dermatology


1 Department of Dermatology and Andrology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission25-Oct-2017
Date of Acceptance31-Dec-2017
Date of Web Publication17-Oct-2019

Correspondence Address:
Heba Allah S K Bazid
Department of Dermatology, Faculty of Medicine, Menoufia University, Shibin Elkom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_716_17

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  Abstract 

Objective
The aim of this study was to assess the role of Notch signaling in both health skin and pathogenesis and management of skin diseases.
Materials and methods
PubMed and all materials on the internet from 2000 to 2017 were searched. The initial search presented 101 articles, of which 49 met the inclusion criteria: clinical trial types II and III, published in English language, published in peer-reviewed journals, and focusing on Notch in different skin diseases. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was obtained, eligibility criteria specified, appropriate controls, and adequate information. A structured systematic review was performed.
Findings
Overall, 49 articles were potentially relevant publications. The studies reported that Notch may have a role in both physiology of the skin and the pathogenesis and treatment of multiple skin diseases.
Conclusion
Notch signaling has many physiological roles, and understanding its role in the pathogenesis of different skin diseases allows new target for their treatment.

Keywords: dermatology, Notch signaling, skin diseases


How to cite this article:
Basha MA, Seleit IA, Bakry OA, Samaka RM, Bazid HA. Notch signaling in dermatology. Menoufia Med J 2019;32:829-35

How to cite this URL:
Basha MA, Seleit IA, Bakry OA, Samaka RM, Bazid HA. Notch signaling in dermatology. Menoufia Med J [serial online] 2019 [cited 2019 Nov 16];32:829-35. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/829/268835




  Introduction Top


Notch signaling has been first described in Drosophila almost 100 years ago, and later it was found to be also present in mammals [1].

Sex-linked lethal mutations in Drosophila were found as homozygous mutations in Notch, which were found to result in cell fate changes during neurogenesis, where heterozygous females had notches in their wings hence the name. Then, the Notch locus was sequenced and shown to encode a transmembrane protein [2].

The Notch family is composed of 4 Notch receptors (Notch-1 to Notch-4) and 5 Notch ligands, including Jagged-1 (JAG-1), JAG-2, δ-like-1, δ-like-3, and δ-like-4 [3].

Both the Notch receptors and their ligands are type I transmembrane proteins. Notch is found at the plasma membrane as a heterodimer composed of a large Notch extracellular domain and a membrane tethered Notch intracellular domain (NICD) [1].

Full-length Notch receptors (1–4) undergo post-translational modifications in the Golgi apparatus to modify the extracellular domain. The Notch receptor is transported to the cell membrane where it exists as a heterodimeric receptor [4].

Notch signal transduction is initiated by ligation of Notch receptors with ligands expressed on neighboring cells [5].

Upon ligand binding, two sequential proteolytic events occur to liberate active NICD. The first cleavage is mediated by a metalloprotease, tumor necrosis factor-α converting enzyme [6]. The final cleavage is performed by a γ-secretase complex, which leads to translocation of the NICD into the nucleus [7].

Within the nucleus, NICD binds to transcription factor, cell binding factor-1/recombination signal binding protein-J (RBP-J), suppressor of hairless, LAG-1 (CSL) where it forms a large transcriptional activation complex together with Mastermind-like (MAML) proteins promoting the activation of CSL-mediated gene transcription [8],[9].

In the absence of the NICD protein, transcription factor CSL is bound to promoter DNA of target genes along with corepressor proteins and activation of downstream targets is repressed. However, in the presence of NICD, co-repressors are displaced, and transcriptional activators, including MAML, activate Notch target genes [4].

Indeed, there are a large number of cell-specific Notch targets as follows:

  1. Transcription factors as members of the Hairy/Enhancer of Split and Hairy/E (spl)-related with YRPW (Hes and Hey) family of bHLH (basic helix–loop–helix)
  2. Genes as cellular gene similar to myelocytomatosis viral oncogene (c-myc), cyclin D, cyclin-dependent kinase 5 (CDK5), and string/cell division cycle 25 (CDC25) where Notch promotes proliferation [10]
  3. Genes as protein 21 (P21) where Notch promotes exit from the cell cycle and differentiation, cell cycle inhibition [11].


The aim of this study was to assess the role of Notch in both healthy skin and pathogenesis and management of skin diseases.


  Materials and Methods Top


Search strategy

We reviewed papers on the role of Notch in both physiology and pathogenesis and management of skin diseases from Medline databases (PubMed, Medscape, Wikipedia, and ScienceDirect) and also materials available on the internet. We used Notch pathogenesis, skin diseases, and physiology as search terms. The search was performed in the electronic databases from 2000 to 2017.

Study selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria: published in English language, published in peer-reviewed journals, focused on Notch in skin diseases, and discussed the role of Notch in the pathogenesis and management of skin diseases.

Data extraction

If the studies did not fulfill the aforementioned criteria, they were excluded, such as studies on Notch in systemic diseases other than skin, report without peer-review, not within national research program, and letters/comments/editorials/news.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the evidence pyramid.

US Preventive Services Task Force classification is as follows:

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed.


  Results Top


Study selection and characteristics

Data sources: PubMed and all materials on the internet from 2000 to 2017 were searched. Study selection: the initial search presented 101 articles, of which 49 met the inclusion criteria: clinical trial types II and III, published in English language, published in peer-reviewed journals, and focusing on Notch in different skin diseases. Data extraction: if the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was obtained, eligibility criteria specified, appropriate controls, and adequate information. Data synthesis: a structured systematic review was performed. Findings: in total, 101 potentially relevant publications were identified, and 62 articles were excluded as they did not meet our inclusion criteria. Therefore, 49 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. Some studies examined the role of Notch in the physiology of the skin. Some studies examined the role of Notch in the pathogenesis of different skin diseases. Some of the studies examined the role of Notch agonists in the treatment of different skin diseases. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.

Role of Notch in the physiology of the skin according to evidence-based medicine

The role of Notch in the physiological function of the skin was investigated in 21 studies [Table 1]. They were case–control studies that come in level II-2 or (level B) EBM or animal studies that comes in the base of the EBM pyramid. The first study indicated its role in stem cell fate and angiogenesis [4], followed by 13 studies that indicated that Notch is involved in the differentiation of both interfollicular epithelium (IFE) and hair follicle (HF) [11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23], two studies that indicated its role in cell metabolism [19],[20], and seven studies that indicated its role in melanocyte lineage [24],[25],[26],[27],[28],[29],[30].
Table 1: Role of Notch in the physiology of the skin

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Role of Notch in the pathogenesis of different skin diseases according to evidence-based medicine

The role of Notch in the pathogenesis of different skin diseases was investigated in 20 studies [Table 2]. They were case–control studies that come in level II-2 or (level B) EBM or animal studies that come in the base of the EBM pyramid. The first two studies indicated its role in vitiligo [28],[31], followed by seven studies that indicated its role in fibroproliferative disorders [32],[33],[34],[35],[36],[37],[38], seven studies that indicated its role in carcinogenesis [23],[39],[40],[41],[42],[43],[44], and four studies that indicated its role in inflammatory disorders [22],[45],[46],[47].
Table 2: Role of Notch in the pathogenesis of different skin diseases

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Role of Notch in the treatment of different skin diseases according to evidence-based medicine

The role of Notch in the treatment of different skin diseases was investigated in three studies [Table 3]. The animal studies come in the base of the EBM pyramid. The first study indicated the role of notch in treatment of vitiligo [48] followed by two studies that indicated its role in other cancer treatment [3],[49].
Table 3: Role of Notch in the treatment of skin diseases

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  Discussion Top


Regarding Notch expression, the IFE shows Notch-1, 2, 3, and 4 expression at the highest levels in the suprabasal cells of the spinous and granular layers, where cells undergo differentiation [12],[13],[14],[15],[16]. This is in accordance with its expression in HFs, where Notches 1, 2, and 3 are expressed in the matrix and precortex of the follicle base [12],[13],[14],[15]. Jagged-1 and Jagged-2 are the only ligands detected in the HFs [13],[14],[17]. Collectively, the studies indicate that Notch activity is associated with differentiation in both the IFE and the growing HF.

Other than differentiation, Notch controls diverse cellular functions such as maintenance of stem cells, cell fate decision, proliferation, differentiation, survival/apoptosis [18], angiogenesis [4] and hypoxia response [19], and is involved in regulation of cellular metabolism [20].

The physiological role of cutaneous Notch signaling has been determined by the analysis of genetically modified mice, for example, skin-specific deletion of RBP-J in mice results in complete ablation of cutaneous Notch signaling:

  1. Ablation during development results in loss of the spinous and granular layers of the IFE, causing severe barrier defects, resulting in death shortly after birth [16]
  2. Ablation of RBP-J in a mosaic fashion thus allows postnatal evaluation of RBP-J-deficient skin [21]. In these mice, the IFE also displays loss of the differentiated layers, but the basal layer is maintained. Moreover, HFs degenerate into large cysts, resulting in complete hair loss
  3. Postnatal deletion of RBP-J in the IFE and HFs resulted in perturbed proliferation and differentiation of the IFE and degeneration of HFs into epidermal cysts [22].


Studies showed that overexpression of N1ICD in the basal layer of the IFE causes severe blistering [16],[17]. This is in agreement with in-vitro experiments that show that Notch induces growth arrest in keratinocytes as well as promotes early stages of differentiation [11],[23].

Moreover, studies showed that Notch signaling plays multiple roles for development and maintenance of the melanocyte lineage, and thus is essential for skin and hair pigmentation [24], and it plays an indispensable role in the maintenance of melanoblasts (MBs) and melanocytes stem cells (MelSCs) of the epidermis [25].

A series of studies elucidated Notch signaling as a key component among keratinocyte–melanocyte interaction through Notch-ligand interactions between the MCs and the surrounding keratinocytes. To proliferate, melanocytes need to decouple from the basement membrane and from the keratinocytes [26],[27]. Diao et al. [28] postulated that inactivation of Notch signaling in the MCs may be a potential pathomechanism of vitiligo and that expression data support that dysregulation of Notch signaling may disturb the balance of the epidermal melanin unit and trigger a continuous proliferation of MCs. Although genetic ablation of Notch signaling in the mouse results in a dramatic reduction of embryonic MBs and MelSCs [29], it plays roles in maintaining the immature status of MBs and promoting its proper localization, while inducing proper MC differentiation in the hair matrix [30].

This was in agreement with Seleit et al. [31] who demonstrated that Notch-1 signaling is inactivated in vitiligo with consequent loss of epidermal and/or follicular active melanocytes, and that the aberrant Notch signaling in vitiliginous white hair and acral and segmental vitiligo may be the cause of their treatment resistance.

Regarding fibrogenesis, it is showed that Notch signaling pathway is involved in both normal wound healing process and keloid and hypertrophic scars by modulating keratinocytes, fibroblasts, and endothelial cells [32] and regulating transforming growth factor β1, which is a principal fibrogenic cytokine promoting the production of the extracellular matrix and tissue fibrosis [33].

A significant upregulation of the NICD in keloid fibroblasts in previous studies was found [32],[34],[35] and that the inhibition of Notch signaling led to the inhibition of proliferation, migration, and invasion properties of keloid fibroblasts [36]. Moreover, Notch signaling pathway also exerts its effects through upstream or downstream signaling transduction of the TGF-β signaling pathway [37],[38].

Notch signaling also has a role in carcinogenesis, as findings show that Notch signaling has a dual action (either as an oncogene or as a tumor suppressor), depending on the tumor cell type and other intracellular signaling mechanisms [39].

Ablation of Notch-1 in the IFE and HFs results in the spontaneous development of basal cell carcinoma (BCC) over time [40]. Notch-1-deficient BCCs show increased expression of the Hedgehog targets glioma-associated oncogenes 1 and2 (Gli1 and Gli2), and Patched, indicating increased activity of the Hedgehog signaling cascade [41].

Skin-specific ablation of Notch-1 in mice also renders these mutants highly susceptible to two-stage chemical carcinogenesis [40],[41] which induces the development of squamous cell carcinoma (SCC) by promoting the expansion of epidermal stem cells carrying H-ras mutations [42].

Another study has subsequently identified loss-of-function mutations in Notch-1 in patient samples of cutaneous SCC, supporting the hypothesis that Notch signaling counteracts cutaneous SCC development [43]. Thus, notch is considered as tumor suppressor of both BCC and SCC.

Although there is increasing evidence that Notch acts as an oncogene in the development of melanomas, with several receptors, ligands, as well as target genes upregulated at early stages of MC transformation and tumor progression [44].

Notch also is linked to inflammatory diseases such as atopic dermatitis, psoriasis, and lichen planus. The mechanism by which Notch signaling is able to regulate inflammation, while unclear, is thought through the repressive relationship with it and activator protien-1, epidermal growth factor receptor signaling, granulocyte macrophage-colony stimulating factor [45].

This is provided by the demonstration that patients with atopic dermatitis show reduced expression of Notch receptors in the epidermis [22].

In psoriasis, Abdou et al. [46] demonstrated that upregulation and not downregulation of Notch-1 may have a role in pathogenesis of psoriasis. The nuclear form is responsible for the exacerbation of symptoms, and it is the one that may disappear by the effect of psoralen and ultraviolet A radiation therapy.

Moreover, it was shown that Notch signaling was dysregulated in cases with oral lichen planus; thus, it may participate in the disease pathophysiology [47].

The Notch signaling could be implicated in many disease therapy such as in vitiligo therapy, as Mou et al. [48] proposed a novel hypothesis for vitiligo treatment using in-situ MC regeneration induced by melanocyte-lineage-specific genes including Notch. This process may promote MC regeneration in situ with little effect on the HF cycling or on carcinogenesis. Moreover, inhibition of Notch signaling has been adopted in clinical trials to treat several malignant tumors [49]. Therefore, Notch signaling appears to be a promising system for new therapeutic targets for the treatment of melanoma and perhaps the prevention of melanoma metastasis [3].


  Conclusion Top


From this review, we could conclude that Notch signaling pathway represents a major research target for understanding the pathogenesis of many skin diseases such as vitiligo and fibrotic skin diseases and using target therapy against Notch in these diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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