Turn It Down a Notch.

Area of Science:

• Developmental Biology
• Molecular Biology
• Cell Biology

Background:

• Embryonic development involves somitogenesis, forming repeated segments (somites).
• The segmentation clock, a molecular oscillator, drives cyclic gene expression in paraxial mesoderm.
• Notch signaling is crucial for synchronizing cell oscillations and somite formation.

Purpose of the Study:

• To review mechanisms regulating the turnover of Notch intracellular domain (NICD).
• To highlight the importance of NICD stability for segmentation clock function.
• To discuss the pathophysiological relevance of NICD regulation.

Main Methods:

• Focuses on existing literature regarding NICD turnover mechanisms.
• Describes the role of phosphorylation and E3 ubiquitin ligase complexes.
• Examines the link between NICD-FBXW7 interaction and diseases.

Main Results:

• NICD is cyclically produced and degraded during somitogenesis.
• Segmentation clock pace is sensitive to NICD levels and stability.
• NICD turnover is regulated by phosphorylation of its PEST domain, recruiting SCF/Sel10/FBXW7.

Conclusions:

• Tightly regulated NICD turnover is essential for somitogenesis and the segmentation clock.
• The NICD-FBXW7 interaction is critical for developmental processes.
• Defects in NICD-FBXW7 interaction are implicated in cancers like leukemia.