ArticleGastroenterology2010
NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network.
Article in Gastroenterology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 129 citations in OpenAlex.
- Camrelizumab plus nimotuzumab as second-line therapy for advanced esophageal squamous cell carcinoma: a multicenter phase II study.Journal for immunotherapy of cancer · 2026Trial
- Trial
- Expression of notch family proteins in placentas from patients with early-onset severe preeclampsia.Reproductive sciences (Thousand Oaks, Calif.) · 2014Trial
- Article
- Genotype-to-Phenotype Mapping of Somatic Clonal Mosaicism via Single-Cell Co-Capture of DNA Mutations and mRNA Transcripts.Cancer discovery · 2026Article
- Prostaglandin EbioRxiv : the preprint server for biology · 2026Article
- Targeting notch signaling pathway in esophageal cancer: from molecular insights to therapies.Oncology reviews · 2026Review
- Modes of Notch signalling in development and disease.Nature reviews. Molecular cell biology · 2025Review
- FOXM1 Modulation Alleviates Epithelial Remodeling and Inflammation in Eosinophilic Esophagitis.bioRxiv : the preprint server for biology · 2025Article
- Epithelial architecture and signaling activity in the adult human esophagus.Frontiers in cell and developmental biology · 2025Review
- Clones in blood and stratified epithelial cells, and their drivers.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2025Review
- Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium.Nature genetics · 2024Article
- Review
- Article
- Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool.Nature communications · 2024Article
- Modeling Radiation-Induced Epithelial Cell Injury in Murine Three-Dimensional Esophageal Organoids.Biomolecules · 2024Article
- ASCL2 is a key regulator of the proliferation-differentiation equilibrium in the esophageal epithelium.Biology open · 2024Article
- Impact of KRAS mutation on the tumor microenvironment in colorectal cancer.International journal of biological sciences · 2024Review
- Esophageal organoids: applications and future prospects.Journal of molecular medicine (Berlin, Germany) · 2023Review
- Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma.Biochemical pharmacology · 2023Review
37 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsThe Notch receptor family regulates cell fate through cell-cell communication. CSL (CBF-1/RBP-jκ, Su(H), Lag-1) drives canonical Notch-mediated gene transcription during cell lineage specification, differentiation, and proliferation in the hematopoietic system, the intestine, the pancreas, and the skin. However, the functional roles of Notch in esophageal squamous epithelial biology are unknown.
methodsNormal esophageal keratinocytes were stimulated with calcium chloride to induce terminal differentiation. The squamous epithelia were reconstituted in organotypic 3-dimensional culture, a form of human tissue engineering. Notch was inhibited in culture with a γ-secretase inhibitor or dominant negative mastermind-like 1 (DNMAML1). The roles of Notch receptors were evaluated by in vitro gain-of-function and loss-of-function experiments. Additionally, DNMAML1 was targeted to the mouse esophagus by cytokeratin K14 promoter-driven Cre (K14Cre) recombination of Lox-STOP-Lox-DNMAML1. Notch-regulated gene expression was determined by reporter transfection, chromatin immunoprecipitation assays, quantitative reverse-transcription polymerase chain reaction, Western blotting, immunofluorescence, and immunohistochemistry.
resultsNOTCH1 (N1) was activated at the onset of squamous differentiation in the esophagus. Intracellular domain of N1 (ICN1) directly activated NOTCH3 (N3) transcription, inducing HES5 and early differentiation markers such as involucrin (IVL) and cytokeratin CK13 in a CSL-dependent fashion. N3 enhanced ICN1 activity and was required for squamous differentiation. Loss of Notch signaling in K14Cre;DNMAML1 mice perturbed esophageal squamous differentiation and resulted in N3 loss and basal cell hyperplasia.
conclusionsNotch signaling is important for esophageal epithelial homeostasis. In particular, the cross talk of N3 with N1 during differentiation provides novel, mechanistic insights into Notch signaling and squamous epithelial biology.
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