Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors

Seymour, Philip A.; Collin, Caitlin; Egeskov-Madsen, Anuska la Rosa; Jørgensen, Mette C.; Shimojo, Hiromi; Imayoshi, Itaru; Lichtenberg, Kristian H. Honnens de; Kopan, Raphael; Kageyama, Ryoichiro; Serup, Palle

doi:10.1101/336529

Cited by 8 publications

(16 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, Hes/Hey can be regulated by other transcriptional factors, such as cyclic adenosine monophosphate (cAMP)-responsive transcription factor (CREB) (45) and hypoxia-inducible factor 1 (HIF1) (46). By corollary, even in the presence of Notch signaling, Hes/Hey genes may not be simultaneously changed because of individual sensitivity to NICD signal intensity and duration, variable mRNA and protein half-lives, or oscillation of target gene expression (47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

Zhu

Wang

et al. 2021

Sci. Transl. Med.

View full text Add to dashboard Cite

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)–modified siRNA, both of which reduced NASH diet–induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.

show abstract

Section: Discussionmentioning

confidence: 99%

Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

Zhu

Wang

et al. 2021

Sci. Transl. Med.

View full text Add to dashboard Cite

show abstract

“…Failure to define this parameter can lead to erroneous conclusions concerning the cellular origins of cells being examined. The Hnf1b -CreER T2 BAC transgenic line has been used by numerous publications to study the progeny of HNF1B-expressing cells in a wide range of experimental models, including cancer, dynamics of cellular differentiation, or regeneration (Jörs, Jeliazkova et al 2015, Kim, Larsen et al 2015, Vieira, Vergoni et al 2018, Seymour, Collin et al 2020). This underscores a need to more fully define its performance.…”

Section: Main Textmentioning

confidence: 99%

Hnf1b-CreER causes efficient recombination of a Rosa26-RFP reporter in duct and islet δ cells

Rovira

Maestro

Grau

et al. 2021

Preprint

View full text Add to dashboard Cite

The Hnf1b-CreERT2 BAC transgenic (Tg(Hnf1b-cre/ERT2)1Jfer) has been used extensively to trace the progeny of pancreatic ducts in development, regeneration, or cancer. This model originally showed that duct-like plexus cells of the embryonic pancreas are bipotent duct-endocrine progenitors, whereas adult mouse duct cells are not a common source of δ cells in various regenerative settings. We have now examined Hnf1b-CreERT2 mice with a Rosa26-RFP reporter transgene. This showed inducible recombination of up to 96% adult duct cells, a much higher efficiency than the previously used β-galactosidase reporter. Despite this high duct-cell excision, recombination in α and β cells remained very low, similar to the previously used reporter transgene (Rosa26-βgalactosidase). However, nearly half of somatostatin-expressing δ cells showed reporter activation, which was due to Cre expression in δ cells rather than an indication of duct to δ cell conversions. The high recombination efficiency in duct cells indicates that the Hnf1b-CreERT2 model can be useful for both ductal fate mapping and genetic inactivation studies. The recombination in δ cells does not modify the interpretation of studies that failed to show duct conversions to other cell types, but needs to be considered in studies that use this model to modify the plasticity of pancreatic duct cells.

show abstract

“…Vitamin D and thyroid hormones induces phosphorylation of vimentin in rat testes, 211,212 whereas the same hormones regulate phosphorylation of vimentin, GFAP, and NFs in rat cerebral cortex 213,214 . IFs may also be involved in generating oscillatory signaling cascades, characteristic for tissue patterning during development through interactions with different signaling molecules 39,215,216 . Cell behavior may be coordinated by IFs through regulation of cell‐cell signaling in multicellular tissues.…”

Section: Mechanisms Of If‐mediated Cell Fate Decisionsmentioning

confidence: 99%

From structural resilience to cell specification — Intermediate filaments as regulators of cell fate

et al. 2020

View full text Add to dashboard Cite

BACKGROUND Cells, just like humans, contain a skeleton providing them with shape, support, and mechanical rigidity. The cellular skeleton, called the cytoskeleton, is made up of different types of fibers such as the actin filaments, microtubules, and intermediate filaments. This review focuses on the intermediate filaments and how they interact with developmental signaling pathways to regulate cell fate decisions. Intermediate filaments (IFs) have tissue-specific

show abstract

Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors

Cited by 8 publications

References 74 publications

Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

Hnf1b-CreER causes efficient recombination of a Rosa26-RFP reporter in duct and islet δ cells

From structural resilience to cell specification — Intermediate filaments as regulators of cell fate

Contact Info

Product

Resources

About