Wnt Signaling in Development and Aging

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 10284

Special Issue Editor


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Guest Editor
1. Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore
2. Division of Science, Yale-NUS College, Singapore 138527, Singapore
Interests: WNT; Drosophila; embryology; development; aging; metabolism; stem cells
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Special Issue Information

Dear Colleagues,

Since its initial discovery nearly 40 years ago, the WNT signalling pathway continues to provide a rich avenue for research. The pathway is highly conserved and regulates a wide range of cellular functions during development and adulthood. For example, in development, it can influence cell proliferation, cell fate determination, apoptosis, cell migration, and cell polarity. In adults, it has been linked to epistasis and stem cell maintenance as well as a range of diseases. This collection will focus on the emerging topics in the wide-ranging field of WNT signalling.

Dr. Nicholas Tolwinski
Guest Editor

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Keywords

  • WNT
  • aging
  • development
  • neurodegeneration
  • stem cells

Published Papers (5 papers)

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Research

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17 pages, 8263 KiB  
Article
The Wnt Co-Receptor PTK7/Otk and Its Homolog Otk-2 in Neurogenesis and Patterning
by Qian Hui Tan, Agimaa Otgonbaatar, Prameet Kaur, Angelica Faye Ga, Nathan P. Harmston and Nicholas S. Tolwinski
Cells 2024, 13(5), 365; https://doi.org/10.3390/cells13050365 - 20 Feb 2024
Viewed by 1286
Abstract
Wnt signaling is a highly conserved metazoan pathway that plays a crucial role in cell fate determination and morphogenesis during development. Wnt ligands can induce disparate cellular responses. The exact mechanism behind these different outcomes is not fully understood but may be due [...] Read more.
Wnt signaling is a highly conserved metazoan pathway that plays a crucial role in cell fate determination and morphogenesis during development. Wnt ligands can induce disparate cellular responses. The exact mechanism behind these different outcomes is not fully understood but may be due to interactions with different receptors on the cell membrane. PTK7/Otk is a transmembrane receptor that is implicated in various developmental and physiological processes including cell polarity, cell migration, and invasion. Here, we examine two roles of Otk-1 and Otk-2 in patterning and neurogenesis. We find that Otk-1 is a positive regulator of signaling and Otk-2 functions as its inhibitor. We propose that PTK7/Otk functions in signaling, cell migration, and polarity contributing to the diversity of cellular responses seen in Wnt-mediated processes. Full article
(This article belongs to the Special Issue Wnt Signaling in Development and Aging)
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18 pages, 4968 KiB  
Article
Ectopic Rod Photoreceptor Development in Mice with Genetic Deficiency of WNT2B
by Alexandra K. Blomfield, Meenakshi Maurya, Kiran Bora, Madeline C. Pavlovich, Felix Yemanyi, Shuo Huang, Zhongjie Fu, Amy E. O’Connell and Jing Chen
Cells 2023, 12(7), 1033; https://doi.org/10.3390/cells12071033 - 28 Mar 2023
Cited by 1 | Viewed by 1594
Abstract
Wnt/β-catenin signaling is essential for embryonic eye development in both the anterior eye and retina. WNT2B, a ligand and activator of the Wnt/β-catenin pathway, assists in the development of the lens and peripheral regions of the eye. In humans WNT2B mutations are associated [...] Read more.
Wnt/β-catenin signaling is essential for embryonic eye development in both the anterior eye and retina. WNT2B, a ligand and activator of the Wnt/β-catenin pathway, assists in the development of the lens and peripheral regions of the eye. In humans WNT2B mutations are associated with coloboma and WNT2B may also assist in retinal progenitor cell differentiation in chicken, yet the potential role of WNT2B in retinal neuronal development is understudied. This study explored the effects of WNT2B on retinal neuronal and vascular formation using systemic Wnt2b knockout (KO) mice generated by crossing Wnt2bflox/flox (fl/fl) mice with CMV-cre mice. Wnt2b KO eyes exhibited relatively normal anterior segments and retinal vasculature. Ectopic formation of rod photoreceptor cells in the subretinal space was observed in Wnt2b KO mice as early as one week postnatally and persisted through nine-month-old mice. Other retinal neuronal layers showed normal organization in both thickness and lamination, without detectable signs of retinal thinning. The presence of abnormal photoreceptor genesis was also observed in heterozygous Wnt2b mice, and occasionally in wild type mice with decreased Wnt2b expression levels. Expression of Wnt2b was found to be enriched in the retinal pigment epithelium compared with whole retina. Together these findings suggest that WNT2B is potentially involved in rod photoreceptor genesis during eye development; however, potential influence by a yet unknown genetic factor is also possible. Full article
(This article belongs to the Special Issue Wnt Signaling in Development and Aging)
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21 pages, 4302 KiB  
Article
N-Glycosylation of LRP6 by B3GnT2 Promotes Wnt/β-Catenin Signalling
by Ruiyao Xu, Xianxian Wang, Sadia Safi, Nico Braunegger, Agnes Hipgrave Ederveen, Michelle Rottmann, Joachim Wittbrodt, Manfred Wuhrer, Janine Wesslowski and Gary Davidson
Cells 2023, 12(6), 863; https://doi.org/10.3390/cells12060863 - 10 Mar 2023
Cited by 1 | Viewed by 2169
Abstract
Reception of Wnt signals by cells is predominantly mediated by Frizzled receptors in conjunction with a co-receptor, the latter being LRP6 or LRP5 for the Wnt/β-catenin signalling pathway. It is important that cells maintain precise control of receptor activation events in order to [...] Read more.
Reception of Wnt signals by cells is predominantly mediated by Frizzled receptors in conjunction with a co-receptor, the latter being LRP6 or LRP5 for the Wnt/β-catenin signalling pathway. It is important that cells maintain precise control of receptor activation events in order to properly regulate Wnt/β-catenin signalling as aberrant signalling can result in disease in humans. Phosphorylation of the intracellular domain (ICD) of LRP6 is well known to regulate Wntβ-catenin signalling; however, less is known for regulatory post-translational modification events within the extracellular domain (ECD). Using a cell culture-based expression screen for functional regulators of LRP6, we identified a glycosyltransferase, B3GnT2-like, from a teleost fish (medaka) cDNA library, that modifies LRP6 and regulates Wnt/β-catenin signalling. We provide both gain-of-function and loss-of-function evidence that the single human homolog, B3GnT2, promotes extension of polylactosamine chains at multiple N-glycans on LRP6, thereby enhancing trafficking of LRP6 to the plasma membrane and promoting Wnt/β-catenin signalling. Our findings further highlight the importance of LRP6 as a regulatory hub in Wnt signalling and provide one of the few examples of how a specific glycosyltransferase appears to selectively target a signalling pathway component to alter cellular signalling events. Full article
(This article belongs to the Special Issue Wnt Signaling in Development and Aging)
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Review

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26 pages, 1374 KiB  
Review
The Multifaceted Role of WNT Signaling in Alzheimer’s Disease Onset and Age-Related Progression
by William W. Kostes and David A. Brafman
Cells 2023, 12(8), 1204; https://doi.org/10.3390/cells12081204 - 21 Apr 2023
Cited by 1 | Viewed by 2274
Abstract
The evolutionary conserved WNT signaling pathway orchestrates numerous complex biological processes during development and is critical to the maintenance of tissue integrity and homeostasis in the adult. As it relates to the central nervous system, WNT signaling plays several roles as it relates [...] Read more.
The evolutionary conserved WNT signaling pathway orchestrates numerous complex biological processes during development and is critical to the maintenance of tissue integrity and homeostasis in the adult. As it relates to the central nervous system, WNT signaling plays several roles as it relates to neurogenesis, synaptic formation, memory, and learning. Thus, dysfunction of this pathway is associated with multiple diseases and disorders, including several neurodegenerative disorders. Alzheimer’s disease (AD) is characterized by several pathologies, synaptic dysfunction, and cognitive decline. In this review, we will discuss the various epidemiological, clinical, and animal studies that demonstrate a precise link between aberrant WNT signaling and AD-associated pathologies. In turn, we will discuss the manner in which WNT signaling influences multiple molecular, biochemical, and cellular pathways upstream of these end-point pathologies. Finally, we will discuss how merging tools and technologies can be used to generate next generation cellular models to dissect the relationship between WNT signaling and AD. Full article
(This article belongs to the Special Issue Wnt Signaling in Development and Aging)
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24 pages, 1456 KiB  
Review
Novel Insights into the Role of Kras in Myeloid Differentiation: Engaging with Wnt/β-Catenin Signaling
by Noriko Yokoyama, Hitoshi Nakayama and Kazuhisa Iwabuchi
Cells 2023, 12(2), 322; https://doi.org/10.3390/cells12020322 - 14 Jan 2023
Cited by 2 | Viewed by 2231
Abstract
Cells of the HL-60 myeloid leukemia cell line can be differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The molecular mechanisms involved in this differentiation process, however, remain unclear. This review focuses on the differentiation of HL-60 cells. Although the Ras [...] Read more.
Cells of the HL-60 myeloid leukemia cell line can be differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The molecular mechanisms involved in this differentiation process, however, remain unclear. This review focuses on the differentiation of HL-60 cells. Although the Ras proteins, a group of small GTP-binding proteins, are ubiquitously expressed and highly homologous, each has specific molecular functions. Kras was shown to be essential for normal mouse development, whereas Hras and Nras are not. Kras knockout mice develop profound hematopoietic defects, indicating that Kras is required for hematopoiesis in adults. The Wnt/β-catenin signaling pathway plays a crucial role in regulating the homeostasis of hematopoietic cells. The protein β-catenin is a key player in the Wnt/β-catenin signaling pathway. A great deal of evidence shows that the Wnt/β-catenin signaling pathway is deregulated in malignant tumors, including hematological malignancies. Wild-type Kras acts as a tumor suppressor during DMSO-induced differentiation of HL-60 cells. Upon DMSO treatment, Kras translocates to the plasma membrane, and its activity is enhanced. Inhibition of Kras attenuates CD11b expression. DMSO also elevates levels of GSK3β phosphorylation, resulting in the release of unphosphorylated β-catenin from the β-catenin destruction complex and its accumulation in the cytoplasm. The accumulated β-catenin subsequently translocates into the nucleus. Inhibition of Kras attenuates Lef/Tcf-sensitive transcription activity. Thus, upon treatment of HL-60 cells with DMSO, wild-type Kras reacts with the Wnt/β-catenin pathway, thereby regulating the granulocytic differentiation of HL-60 cells. Wild-type Kras and the Wnt/β-catenin signaling pathway are activated sequentially, increasing the levels of expression of C/EBPα, C/EBPε, and granulocyte colony-stimulating factor (G-CSF) receptor. Full article
(This article belongs to the Special Issue Wnt Signaling in Development and Aging)
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