Notch1 cortical signaling regulates epithelial architecture and cell-cell adhesion

Area of Science:

• Cell Biology
• Developmental Biology
• Epithelial Biology

Background:

• Notch receptors regulate tissue development through cell architecture and gene expression changes.
• The precise mechanisms by which Notch receptors achieve diverse biological outcomes remain incompletely understood.
• Understanding Notch signaling is crucial for comprehending tissue morphogenesis and homeostasis.

Purpose of the Study:

• To investigate the role of Notch1 in human ductal epithelial morphogenesis.
• To differentiate the contributions of transcriptional and non-transcriptional Notch1 signaling pathways.
• To elucidate the molecular mechanisms underlying Notch1-mediated control of cell architecture and adhesion.

Main Methods:

• Utilized a 3D human ductal epithelium model.
• Analyzed tissue morphogenic defects upon loss of Notch1.
• Investigated Notch1 localization, cortical signaling, and interactions with FAM83H.

Main Results:

• Loss of Notch1, but not its transcriptional signaling, caused duct morphogenesis defects.
• Defects were linked to dysregulated epithelial cell architecture and mitogenic signaling.
• A transcription-independent Notch1 cortical signaling pathway stabilizes adherens junctions and cortical actin via FAM83H interaction.

Conclusions:

• Notch1 controls duct morphogenesis through a non-transcriptional mechanism regulating cell architecture.
• This pathway involves stabilization of adherens junctions and cortical actin, mediated by FAM83H.
• Proposes a paradigm where Notch1 coordinates transcriptional and cell adhesion programs.