Notch-Dll4 lateral inhibition and tip/stalk cell selection

Before the Notch pathway is considered, the idea of lateral inhibition appears in chemical pattern models. Durant and colleagues (2016) describe how Meinhardt and Gierer, inspired by Turing's reaction-diffusion work, proposed systems built on local self-activation and long-range lateral inhibition.² These systems generate specific patterns from near-homogeneous states or perturbations.² Durant and colleagues report that such models can explain polarity, re-patterning and scaling in planarian worms after surgery.² Those models rest on diffusible chemical species. Notch signalling, described below, works between adjacent cells.³

Newman (2019) describes lateral inhibition as a local choice between alternative cell fates, usually mediated by Notch.³ A Notch receptor binds a membrane-bound ligand of the Delta, Serrate or Lag-2 class. The intracellular part of Notch then moves to the nucleus and switches CSL factors from repressors to activators.³ Newman adds that the target gene Hes1 regulates itself by negative feedback, so Hes1 levels tend to oscillate.⁴ He argues that coupled oscillators can synchronize across a tissue, which supports a morphogenetic field.⁴ Davies and Glykofrydis (2020) note that activation in trans and repression in cis is a feature of Notch signalling, and they describe a synthetic circuit built on it.⁵

The currently accepted view of blood vessel sprouting is that new tip cells are selected by Notch-Dll4 lateral inhibition, triggered mainly by Vegf released from hypoxic tissue.⁷ Zakirov and colleagues (2021) argue that this accepted account is incomplete because it ignores timing. Lateral inhibition needs several cycles of gene expression to amplify small differences in Vegf input, which seems incompatible with the fast changes seen in angiogenesis.⁷ They report that tip cell selection is a time-constrained step in zebrafish intersegmental vessel formation.⁷ Their model predicts that structuring of the sensed signal biases one cell to win before lateral inhibition commits the choice.⁸

Several authors connect Notch to ion transport and voltage. Monteiro and colleagues (2014) cite earlier studies showing that the V-ATPase is essential for Notch activation by regulating endosomal pH.¹ Pai and colleagues (2020) cite earlier studies (Pai 2015b, 2018; Herrera-Rincon 2017) showing that setting voltage prepatterns with specific channels can rescue neural patterning defects caused by aberrant Notch signalling.⁶ George and Bates (2022) review the reverse direction. In HEK293 cells, Notch signalling reduces voltage-gated potassium channel activity and drives calcium influx, so Notch may both regulate and be regulated by ion channels.⁹