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This study explored the functions of wnt pathways, both canonical and noncanonical, in the development of murine eyelids. Transgenic mice were used as model organisms to explore the Wnt signaling pathway in eyelid development. Experiments were conducted that blocked various parts of Wnt/β-catenin signaling in the mesenchyme of the upper eyelid. When β-catenin and Wnt ligands, like WNTLESS (Wls), were deleted there was a decrease in cell proliferation and decrease in Wnt target genes Lef1 and Twist1. The overall downregulation of the Wnt pathway resulting from different approaches of the experiments indicates Wnt/β-catenin signaling is required for appropriate eyelid development.
The disruption of the signaling pathway at different points results in eyes open at birth (EOB) embryonic phenotypes in the mice which are consistent with what we see in abnormal human fetuses with eyelid colobomas. Eyelid colobomas are characterized by partial or total loss of eyelid tissue. Data are crucial for human applications such as understanding fetuses born with eyelid abnormalities and how we can begin to treat such syndromes present at birth.
The study also focused on FGF10, whether the expression was affected in Wls mutant embryos. It was found that FGF10 expression is dependent on secretion of epithelial Wnt ligands. Finally, deletion of p63 was investigated. P63 is a gene that belongs to the same protein family as p53 and p73. P63 determines the fate of ectoderm-derived tissues and is essential for epithelial development. This paper found that homozygous p63 mutants had smaller eyelids and parts of the Wnt pathway were downregulated, thus p63 has a role in regulating the expression of genes in the Wnt/β-catenin signaling pathway.
Links related to the paper:
Gene-Environment interactions target MAP3K1 in Eyelid Morphogenesis
Signaling Pathways in Morphogenesis of Cornea and Eyelid
Congenital Upper Eyelid Coloboma: All perspectives
p63 in corneal and epithelial differentiation
FGF10 is a mesenchymal derived stimulator for epidermal development in chicks
This article explores the role of O-GlcNAcylation in cerebellum development and its potential involvement in medulloblastoma oncogenesis through the Sonic Hedgehog (SHH) signaling pathway. The study suggests that O-GlcNAcylation plays a promoting role in cerebellum development. Additionally, the researchers propose a potential link between O-GlcNAcylation and the oncogenesis of medulloblastoma, a type of brain tumor, by influencing the SHH signaling pathway. The Sonic Hedgehog pathway is known to be crucial in the development of various tissues, and the dysregulation of this pathway has been associated with cancer.
The SHH pathway promotes and maintains the proliferation of the granule neuron precursors. The SHH pathway as we have learned controls key stages and parts during growth and development. SHH is important for making sure that the growth pattern and specification of the cerebellum is correct. The researchers wanted to see the effects of O-GlyNAcylation (which is a protein that was discovered to be regulator of neurodevelopment)on the SHH pathway under the presence of cancerous medulloblastoma (which is cancerous tumor in the central nervous system which is found in the cerebellum in children). The paper proposes that if the O-GlyNA protein is present in the infected SHH area, then O-GlyNA will be able to activate and maintain the SHH pathway to allow for proliferation of healthy cells in the developmental stages of the cerebellum and then this will allow for medical professionals and scientist to pinpoint target a therapeutic process to mediate the SHH that is associated will the growth of the medulloblastoma.
The paper shows that factors such as the way that OGT (which is O-GluNAcylation in SHH within the GLI family zinc finger 2) will promote the deacetylation and transcriptional activity in p300 (a histone) causing a histone acetyltransferases. But by OGT inhibition or chemical inhibition, the medulloblastoma increases in survival rate thus showing that the O-GlyNAc signaling plays a huge role in treating and researching patients with medulloblastoma.
Links related to the paper:
Cerebellum development during childhood and adolescence: A longitudinal morphometric MRI study
Principles of tumorigenesis and emerging molecular drivers of SHH-activated medulloblastomas
SHH Pathway and Cerebellar Development
O-GlcNAcylation: a new cancer hallmark?
This study explored the role of the p53 protein in therapeutic cancer treatment. Full p53 activity is required for proper tumor suppression as even a partial loss of p53 function can increase the risk of cancer. Full reactivation of p53 is shown to be difficult with current preclinical and clinical testing. Thus, this study uses the p53 variant E177R, that was genetically modified using a conditional knock-in mouse, to suggest that partial p53 reactivation is sufficient enough to induce cancer regression.
Previous studies demonstrate that many p53-deficient tumors are strongly addicted to the absence of p53 activity and regress when p53 is restored. How much p53 activity was needed to induce tumor regression was unclear. This study observed that the p53 variant E177R with partial reactivation of p53 was enough to inhibit proliferation, viability, and trigger cancer regression in vivo when introduced to p53-deficient leukemia and lymphomas in mice. The p53 variant used in this study can typically increase cancer susceptibility and promote the development of leukemia and lymphoma by itself. However, when induced to p53-deficient tumors, it can induce therapeutic cancer treatment. This demonstrates that p53 mutants function in a highly context specific manner, and how sensitive cancer cells respond to changes in p53 activity.
The mice used in this study had strong responses to partial reactivation of p53. However, they were not fully cured and eventually relapsed. Relapsed mice had high-level expression of the E177R mutation, suggesting that tumor cells may eventually adapt and tolerate the E177R activity. Despite this, this transient response may still be useful in acute myeloid leukemia patients. The temporary inhibitory response can provide clinical remission needed for a bone marrow transplant as the final curative treatment.
Links related to the paper:
Treating p53 Mutant Aggregation-Associated Cancer
Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas
Cancer Therapy by Reactivation of the p53 Apoptosis Pathway
p53 Partial loss-of-function Mutations Sensitize to Chemotherapy
Activation of two oncogenes, MYC and β-catenin, together strongly accelerates the development of liver cancer. Investigation into this process also identified a set of genes that are activated by both MYC and β-catenin, and found that two transcriptional coactivators, YAP and TAZ, play a role in promoting tumor growth and survival. The findings of this paper suggest that targeting Yap and Taz could be a potential therapeutic strategy for liver tumors specifically with high MYC and β-catenin activity.
By using a specific breed of mice that allowed for conditional activation of MYC and WNT/β-catenin signaling, the study could monitor their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. They specifically used this mouse model to study these changes and found that activation of β-cat alone caused minimal transcriptional changes compared to normal livers. However, activation of MYC resulted in regulation of nearly 3,000 genes. Focusing on 125 genes that showed higher expression levels when both oncogenes were active compared to just MYC alone, they found that these genes enriched for targets regulated by YAP and TAZ. This shows an association with MYC and WNT pathways through YAP/TAZ which leads to enhanced liver tumorigenesis.
Overall, these findings suggest a connection between WNT/β-catenin signaling and Myc related proliferation. This leads to an understanding of why cooperation between these two pathways is important for liver tumorigenesis. To apply this idea to humans, they reanalyzed gene expression profiles of patient cohorts, and observed that the MYC/β-catenin signature identified in the study was enriched in a subset of HCC patients, in which correlated with worse prognosis. Targeting and deleting YAP or TAZ has shown limited negative effects on normal tissues, and could reduce HCC proliferation.
Links related to the paper:
Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets - Article talks about identifying genes in analysis of liver tumors in order to improve tumor characterization to optimize personalized treatment.
YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC
Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas - Builds on the main article to investigate the role of HCC signaling in liver carcinogenesis. They do this by creating mouse Apc mutants and conclude that activation of the Wnt/β-catenin pathway by invalidation of Apc is required for liver tumorigenesis.
TAZ is indispensable for c-MYC-induced hepatocarcinogenesis
This paper focuses on the limb development in marine mammals, mainly focusing on the pantropical spotted dolphin as a model for the molecular origins of mammalian hyperphalangy. Hyperphalangy is a phenotype where there is an increase in the number of phalanges on a digit, exceeding the mammalian plesiomorphic condition of three phalanges per digit. Cetaceans (a taxonomic family consisting of large aquatic mammals such as whales, dolphins, and porpoises) are the only mammals to display the hyperphalangy phenotype, displaying an average of 4-5 phalanges on a digit and, in extreme cases, up to 17. This is believed to be attributed to a difference in apical ectodermal ridge (AER) morphology during early limb development, since consistency was observed between pigs and mice but differed in dolphins.
Additionally, spatiotemporal patterns of signaling proteins, which are key in shaping mammalian limbs, in embryos of dolphins, pigs, and mice were very similar. However, fetal dolphins failed to undergo apoptosis and retained tissue in between their digits. This interdigital retention, in addition to multiple waves of interdigital signals, are said to contribute to the development of supernumerary joints and phalanges expressed in dolphins.
When comparing fossil records to experimental findings, researchers found evidence suggesting that interdigital webbing found in early semi-aquatic cetacean ancestors likely resulted from BMP-antagonists preventing apoptosis in the interdigital region during early limb development. Various forms of hyperphalangy, while independently evolved in different cetacean species, are likely associated with modifications in signaling waves within the interdigital tissues.
Links related to the paper:
Neuromuscular Anatomy and Evolution of the Cetacean Forelimb
Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis
Evolution of hyperphalangy and digit reduction in the cetacean manus
Wnt/β-catenin signaling is sufficient and necessary for synovial joint formation
Triple negative breast cancer (TNBC) is one of the most challenging breast cancers to treat and results in poorer outcomes compared to other breast cancers. TNBC lacks estrogen and progesterone hormone receptors and thus is not a good candidate for the current array of targeted therapies. This study focuses on the upregulation of Frizzled-7 proteins in tumors and the effects of that over-expression on the Wnt/β-catenin pathway. Multiple studies have shown that activation of the Wnt/B-catenin pathway is instrumental in facilitating tumor growth, cancer cell migration, and invasion. By disrupting the upregulation of Frizzled-7, it could be possible to limit tumor growth and metastasis.
Xie et al. generated a recombinant extracellular peptide of human Fzd7 (rhFzd7). When introduced, rhFzd7 competed with Frizzled-7 by binding the Wnt ligands and preventing them from binding to Frizzled-7. The result was blocking of the Wnt/β-catenin pathway, which proliferation of cells and angiogenesis, (development of vascular system which supports tumors).
This study also found that rhFzd7 also succeeded in sensitizing TNBC cells to Docetaxol, which is a treatment currently used with some success in treating this form of breast cancer. By using mice as an animal model, researchers were able to demonstrate that Docetaxol plus rhFzd7 inhibited tumor growth.
Links related to the paper:
FH535 Inhibited Migration and Growth of Breast Cancer Cells
Structural Basis of Wnt Recognition by Frizzled
Frizzled7 Functions as a Wnt Receptor in Intestinal Epithelial Lgr5+ Stem Cells