Abstract
The evolutionarily conserved NOTCH signaling displays pleotropic functions in almost every organ system with a simple signaling axis. Different from many other signaling pathways that can be amplified via kinase cascades, NOTCH signaling does not contain any intermediate to amplify signal. Thus, NOTCH signaling can be activated at distinct signaling strength levels, disruption of which leads to various developmental disorders. Here, we reviewed mechanisms establishing different NOTCH signaling strengths, developmental processes sensitive to NOTCH signaling strength perturbation, and transcriptional regulations influenced by NOTCH signaling strength changes. We hope this could add a new layer of diversity to explain the pleotropic functions of NOTCH signaling pathway.
Highlights
Since the observation of notched wing in Drosophila and subsequent discovery of notch gene one century ago (Morgan, 1917), NOTCH signaling has been extensively studied
Suppressing of notch intracellular domain (NICD) dimerization leads to various developmental disorders including heart anomalies and defective marginal zone B (MZB) cell differentiation; shifted balance between dimerized NICD and monomer NICD that can be influenced by NICD dosage is going to affect transcriptional profile as well (Hass et al, 2015; Kobia et al, 2020)
The on/off switch of NOTCH signaling is well-recognized for its function on regulating cell differentiation, proliferation, and apoptosis
Summary
Since the observation of notched wing in Drosophila and subsequent discovery of notch gene one century ago (Morgan, 1917), NOTCH signaling has been extensively studied. Previous studies reviewed that protein level reduction caused by heterozygous mutation of NOTCH signaling components can lead to multiple developmental defects Since CSL and other transcriptional co-factors are always readily present in cell nucleus, the level of NICD generated determines the strength and duration of NOTCH signaling.
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