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Molecular Mechanisms behind the Wnt Signalling Pathways

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Genetics and Genomics".

Deadline for manuscript submissions: closed (24 February 2023) | Viewed by 9583

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Special Issue Editors

Dr. Mark Agostino

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Guest Editor

1. Curtin Health and Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
2. Curtin Institute for Computation, Curtin University, Bentley, WA 6102, Australia
Interests: structural biology; molecular simulation; structure-based drug design; Wnt signalling; carbohydrate–protein interactions

Dr. Sebastian Other-Gee Pohl

E-Mail Website
Guest Editor

Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Midlothian EH4 2XU, UK
Interests: Wnt signalling; colorectal cancer; intestinal cell plasticity; RNA splicing

Special Issue Information

Dear Colleagues,

The Wnt signalling pathways underpin embryonic and organ development as well as tissue homeostasis. The dysregulation of these pathways, in particular, the b-catenin-dependent pathway, can result in oncogenesis and impaired stem-cell function. Accordingly, Wnt-signalling-pathway components are of interest as potential therapeutic targets in the treatment of cancer and in molecular biotechnological applications. The aim of this Special Issue is to provide a contemporary update on the latest studies of these fascinating pathways.

In this Special Issue, we welcome the following submissions:

Original research articles investigating molecular, cellular, and preclinical studies on Wnt signalling;
Reviews covering recent studies of Wnt signalling and its relevance to specific aspects of biology;
Technical reports detailing new in silico, in vitro, and in vivo methodologies for the study of Wnt signalling in diseases and biotechnology;
Opinions and perspectives covering new hypotheses on Wnt signal transduction and the role of Wnt signalling in mediating specific cellular and whole-organ developmental processes.

We look forward to receiving your contributions.

Dr. Mark Agostino
Dr. Sebastian Other-Gee Pohl
Guest Editors

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. Biology 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

Wnt signaling
molecular biology
cancer
stem cells
oncogenic signaling
development

Published Papers (4 papers)

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Research

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22 pages, 11045 KiB

Open AccessArticle

Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation

by Ploy Adisornkanj, Rajit Chanprasit, Steven Eliason, Juan M. Fons, Worrachet Intachai, Sissades Tongsima, Bjorn Olsen, Stefan T. Arold, Chumpol Ngamphiw, Brad A. Amendt, Abigail S. Tucker and Piranit Kantaputra

Biology 2023, 12(3), 393; https://doi.org/10.3390/biology12030393 - 1 Mar 2023

Cited by 2 | Viewed by 1937

Abstract

A mesiodens is a supernumerary tooth located in the midline of the premaxilla. To investigate the genetic cause of mesiodens, clinical and radiographic examination were performed on 23 family members of a two-generation Hmong family. Whole exome sequencing (WES) or Sanger sequencing were performed in 22 family members and two unrelated Thai patients with mesiodens. WES in the Hmong family revealed a missense mutation (c.1807G>A;p.Glu603Lys) in PTPN23 in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in PTPN23, c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. PTPN23 is a regulator of endosomal trafficking functioning to move activated membrane receptors, such as EGFR, from the endosomal sorting complex towards the ESCRT-III complex for multivesicular body biogenesis, lysosomal degradation, and subsequent downregulation of receptor signaling. Immunohistochemical study and RNAscope on developing mouse embryos showed broad expression of PTPN23 in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, PTPN23 mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in PTPN23, suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms behind the Wnt Signalling Pathways)

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12 pages, 3201 KiB

Open AccessArticle

Rare Variants in LRP4 Are Associated with Mesiodens, Root Maldevelopment, and Oral Exostoses in Humans

by Piranit Nik Kantaputra, Peeranat Jatooratthawichot, Ploy Adisornkanj, Panita Kitsadayurach, Massupa Kaewgahya, Bjorn Olsen, Atsushi Ohazama, Chumpol Ngamphiw, Sissades Tongsima, Timothy C. Cox and James R. Ketudat Cairns

Biology 2023, 12(2), 220; https://doi.org/10.3390/biology12020220 - 30 Jan 2023

Cited by 4 | Viewed by 2452

Abstract

Background: Low density lipoprotein receptor-related protein 4 (LRP4; MIM 604270) modulates WNT/β-catenin signaling, through its binding of WNT ligands, and to co-receptors LRP5/6, and WNT inhibitors DKK1, SOSTDC1, and SOST. LRP4 binds to SOSTDC1 and WNT proteins establishing a negative feedback loop between Wnt/β-catenin, Bmp, and Shh signaling during the bud and cap stages of tooth development. Consistent with a critical role for this complex in developing teeth, mice lacking Lrp4 or Sostdc1 have multiple dental anomalies including supernumerary incisors and molars. However, there is limited evidence supporting variants in LRP4 in human dental pathologies. Methods: We clinically, radiographically, and molecularly investigated 94 Thai patients with mesiodens. Lrp4 mutant mice were generated in order to study the effects of aberrant Lrp4 expression in mice. Results: Whole exome and Sanger sequencing identified three extremely rare variants (c.4154A>G, p.Asn1385Ser; c.3940G>A, p.Gly1314Ser; and c.448G>A, p.Asp150Asn) in LRP4 in seven patients with mesiodens. Two patients had oral exostoses and two patients had root maldevelopments. Supernumerary incisors were observed in Lrp4 mutant mice. Conclusions: Our study implicates heterozygous genetic variants in LRP4 as contributing factors in the presentation of mesiodens, root maldevelopments, and oral exostoses, possibly as a result of altered WNT/β-catenin-BMP-SHH signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms behind the Wnt Signalling Pathways)

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Review

Jump to: Research

32 pages, 1648 KiB

Open AccessReview

Wnt Signaling in Brain Tumors: A Challenging Therapeutic Target

by Lorenzo Manfreda, Elena Rampazzo and Luca Persano

Biology 2023, 12(5), 729; https://doi.org/10.3390/biology12050729 - 16 May 2023

Cited by 3 | Viewed by 2421

Abstract

The involvement of Wnt signaling in normal tissue homeostasis and disease has been widely demonstrated over the last 20 years. In particular, dysregulation of Wnt pathway components has been suggested as a relevant hallmark of several neoplastic malignancies, playing a role in cancer onset, progression, and response to treatments. In this review, we summarize the current knowledge on the instructions provided by Wnt signaling during organogenesis and, particularly, brain development. Moreover, we recapitulate the most relevant mechanisms through which aberrant Wnt pathway activation may impact on brain tumorigenesis and brain tumor aggressiveness, with a particular focus on the mutual interdependency existing between Wnt signaling components and the brain tumor microenvironment. Finally, the latest anti-cancer therapeutic approaches employing the specific targeting of Wnt signaling are extensively reviewed and discussed. In conclusion, here we provide evidence that Wnt signaling, due to its pleiotropic involvement in several brain tumor features, may represent a relevant target in this context, although additional efforts will be needed to: (i) demonstrate the real clinical impact of Wnt inhibition in these tumors; (ii) overcome some still unsolved concerns about the potential systemic effects of such approaches; (iii) achieve efficient brain penetration. Full article

(This article belongs to the Special Issue Molecular Mechanisms behind the Wnt Signalling Pathways)

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12 pages, 1439 KiB

Open AccessReview

Understanding the Wnt Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Feasible Key against Relapses

by Daniel Láinez-González, Ana Belén Alonso-Aguado and Juan Manuel Alonso-Dominguez

Biology 2023, 12(5), 683; https://doi.org/10.3390/biology12050683 - 5 May 2023

Cited by 3 | Viewed by 2265

Abstract

Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML. Full article

(This article belongs to the Special Issue Molecular Mechanisms behind the Wnt Signalling Pathways)

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