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Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network
Shinya Ohashi1, Mitsuteru Natsuizaka, Yumi Yashiro-Ohtani
1Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Gastroenterology
|August 31, 2010
Summary
Notch signaling, particularly the interaction between NOTCH1 and NOTCH3, is crucial for esophageal squamous epithelial differentiation and homeostasis. This study reveals key mechanisms underlying this process.
Area of Science:
- Cell biology
- Developmental biology
- Molecular biology
Background:
- The Notch receptor family regulates cell fate via cell-cell communication.
- CSL transcription factor drives Notch-mediated gene expression in various tissues.
- The role of Notch in esophageal squamous epithelium remains largely unknown.
Purpose of the Study:
- To investigate the functional roles of Notch signaling in esophageal squamous epithelial biology.
- To elucidate the specific Notch receptors and pathways involved in esophageal differentiation.
Main Methods:
- Organotypic 3D culture of esophageal keratinocytes.
- Inhibition of Notch signaling using a γ-secretase inhibitor or dominant-negative mastermind-like 1 (DNMAML1).
- In vivo studies using K14Cre;DNMAML1 mice to assess Notch loss-of-function in the esophagus.
Main Results:
- NOTCH1 (N1) activation initiates esophageal squamous differentiation.
- N1's intracellular domain (ICN1) activates NOTCH3 (N3) transcription, promoting differentiation markers.
- N3 is essential for N1 activity and squamous differentiation; its loss causes hyperplasia in mice.
Conclusions:
- Notch signaling is vital for maintaining esophageal epithelial homeostasis.
- Cross-talk between N1 and N3 during differentiation offers new insights into esophageal squamous biology.
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