systematic-scoring-analysis-for-intestinal-inflammation-murine

Systematic Scoring Analysis for Intestinal Inflammation in a Murine Dextran Sodium Sulfate-Induced Colitis Model

Murine colitis models are tools that are extensively employed in studies focused on understanding the pathobiology of inflammatory intestinal disorders. ...

linköping university

The canonical Wnt/β-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers.

Extrinsic control of Wnt signaling in the intestine.

Chronic inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are a major health burden worldwide. Numerous conserved signaling pathways control tissue injury and repair during colitis, but owing to the complexity of the inflammatory process, their individual contribution remains poorly understood. A key regulatory pathway in the intestinal mucosa is Wnt/β-catenin signaling, which acts as the central organizer of epithelial stem cell identity and maintenance. Apart from this core function, there is mounting evidence that the Wnt pathway is highly interconnected with numerous other signaling cascades, and that combinatorial signaling events shape epithelial homeostasis and tissue regeneration. Here we provide an updated view of how Wnt signaling intersects with major inflammatory pathways, with a particular focus on intestinal inflammation. Elucidating the reciprocal actions of Wnt ligands and cytokines has the potential to reveal new treatment options for chronic colitis and other inflammatory disorders.

Wnt signaling in intestinal inflammation.

Who controls the Wnt?

The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple Wnt ligands, including WNT7B, which increases TCF/LEF-dependent transcription without activating Wnt coreceptor LRP6 or β-catenin. Proximity ligation and functional complementation assays identified several transcription regulators, including YY1, JUN, and DDX5, as cofactors required for FOXB2-dependent pathway activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 controls Wnt signaling and neuroendocrine differentiation of prostate cancer cell lines. Our results suggest that FOXB2 is a tissue-specific Wnt activator that promotes the malignant transformation of prostate cancer.

Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer.

Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs].

The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis.

Forkhead box (FOX) family transcription factors play essential roles in development, tissue homeostasis, and disease. Although the biology of several FOX proteins has been studied in depth, it is unclear to what extent these findings apply to even closely related family members, which frequently exert overlapping but non-redundant functions. To help address this question, we have generated a uniform, ready-to-use expression library of all 44 human FOX transcription factors with a convenient peptide tag for parallel screening assays. In addition, we have generated multiple universal forkhead box reporter plasmids, which can be used to monitor the transcriptional activity of most FOX proteins with high fidelity. As a proof-of-principle, we use our plasmid library to identify the DNA repair protein XRCC6/Ku70 as a selective FOX interaction partner and regulator of FOX transcriptional activity. We believe that these tools, which we make available via the Addgene plasmid repository, will considerably expedite the investigation of FOX protein biology.

Article	Year
Extrinsic control of Wnt signaling in the intestine. Differentiation; research in biological diversity\| PubMed ID: 28802143	2017
Wnt signaling in intestinal inflammation. Differentiation; research in biological diversity\| PubMed ID: 30718056	2019
Who controls the Wnt? Differentiation; research in biological diversity\| PubMed ID: 31239179	2019
Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 31611391	2019
The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis. Journal of Crohn's & colitis\| PubMed ID: 32016376	2020
A uniform expression library for the exploration of FOX transcription factor biology. Differentiation; research in biological diversity\| PubMed ID: 32858261	2020

Stefan Koch

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