Notch signaling is an evolutionary conserved pathway that regulates several cellular processes including cell fate specification, migration, proliferation and differentiation. Notch signaling was first described in a Drosophila mutant and earned its name based on a notched-wing phenotype. Notch proteins were subsequently cloned in vertebrates and pathway components knocked out in mouse models. Further studies have illustrated that Notch signaling regulates embryonic development of a multitude of derivatives including vascular development, cardiogenesis, skeletogenesis, central and enteric nervous system development, neural crest cell development, and has been shown to act as an oncogene or tumor suppressor in cancer.
Fig. 1 Overview of the Notch signaling pathway. Figure adapted from Hori et al. (2013).
In mammals there are four Notch receptors and five Notch ligands. Each membrane-bound receptor (Notch1, Notch2, Notch3, Notch4) has an extracellular domain involved in ligand binding and an intracellular domain involved in signal transduction. There are five membrane-bound mammalian Notch ligands (DeltaA, DeltaC, DeltaD, Jagged1, and 2) that contain an amino-terminal domain known as DSL, and a variable number of EGF-like repeats. Notch signaling is initiated through ligand-receptor binding between neighboring cells. This binding results in a conformational change that allows tumor necrosis factor α conversion enzyme (TACE), an ADAM protease, to cleave the receptor on the extracellular side, while a γ-secretase complex mediates a second cleavage near the transmembrane domain, liberating the Notch receptor intracellular domain (NICD). NICD subsequently translocates to the nucleus where it binds to the transcription factor CSL (also known as CBF1 in human, Suppressor of Hairless in Drosophila, LAG2 in Carnorhabditis elegans and recombination signal binding protein for immunoglobulin kappa J (RBP-J) in mice). This binding, along with co-activators, such as mastermind-like (MAML) and histone acetyltransferase, displaces the co-repressor complex of SMRT/NcoR and SHARP/MINT/SPEN and changes RBP-J from a transcriptional repressor into a transcriptional activator. Together, this binding complex ultimately activates expression of downstream target genes, such as basic helix-loop-helix transcriptional repressors related to Hairy enhancer of split (Hes1, 5, 7), or Hes-related with YRPW motif (Hey1, 2, and L), to affect many cellular processes including cell proliferation and differentiation.
Notch and the cell cycle
Notch pathway also coordinates with the cell cycle and apical-basal polarity during retinal development through the interkinetic nuclear migration described above. Del Bene et al have demonstrated that in the zebrafish retinal neuroepithelium, the anti-neurogenic Notch activity is predominantly activated at the apical side. Previous observations have reported that the selection of postmitotic neuronal daughter cells from progenitors is linked to RPC apical-basal polarity. In line with this, the expression of Notch pathway components and their effector genes are cell-cycle dependent, such that Notch activity reaches its maximum level during M phase (when RPC nuclei are located apically), and drops dramatically during S phase (when RPC nuclei are located basally). Together these findings suggest that in the retinal neuroepithelium, apical-basal Notch gradient and interkinetic nuclear migration allow the cell to be exposed to neurogenic versus proliferative signals, which in turn regulate cell-cycle exit.