Redundancy and cooperation in Notch intercellular signaling

Abstract

During metazoan development, Notch signaling drives spatially coordinated differentiation by establishing communication between adjacent cells. This occurs through either lateral inhibition, in which adjacent cells acquire distinct fates, or lateral induction, in which all cells become equivalent. Notch signaling is commonly activated by several distinct ligands, each of which drives signaling with a different efficiency upon binding to the Notch receptor of adjacent cells. Moreover, these ligands can also be distinctly regulated by Notch signaling. Under such complex circumstances, the overall spatial coordination becomes elusive. Here, we address this issue through both mathematical and computational analyses. Our results show that when two ligands have distinct efficiencies and compete for the same Notch receptor, they cooperate to drive new signaling states, thereby conferring additional robustness and evolvability to Notch signaling. Counterintuitively, whereas antagonistically regulated ligands cooperate to drive and enhance the response that is expected from the more efficient ligand, equivalently regulated ligands coordinate emergent spatial responses that are dependent on both ligands. Our study highlights the importance of ligand efficiency in multi-ligand scenarios, and can explain previously reported complex phenotypes.

Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development

“…Second, redundancy among the multiple Notch ligands and receptors may exist for key processes. 29 Third, Notch signaling in different cell types seem to have opposing effects on atherogenesis. It facilitates or antagonizes inflammatory cell recruitment to endothelium in different contexts, 30,31 regulate polarization of macrophages, 32 and, as shown here, inhibits recruitment of SMC-derived plaque cells while being required for their contribution to the cap SMC population.…”

Multistability and transitions between spatiotemporal patterns through versatile Notch-Hes signaling

“…In addition, signal-driven transition from a stable spatiotemporal pattern toward a given spatial pattern can operate as a both robust and flexible canalization process to the desired multicellular outcome. This mechanism is complementary to pattern selection and fine-tuning mechanisms mediated by the developmental modulation of Delta-Notch interactions and/or Notch-Delta intracellular signaling (Formosa-Jordan and Ibañes, 2014;Palau-Ortin et al, 2015;Boareto et al, 2015;Sato et al, 2016;Luna-Escalante et al, 2018). This issue of pattern selection is illustrated by the differences observed during neurogenesis and somitogenesis where a similar circuit gives rise either to dynamic salt-and-pepper patterns or traveling waves (Liao and Oates, 2017;Kageyama et al, 2018).…”

Promotion of In Vitro Hair Cell-like Cell Differentiation from Human Embryonic Stem Cells through the Regulation of Notch Signaling

“…The activation of the Notch signaling pathway promotes the formation of otic precursor cells during the early development of the inner ear. However, Notch signaling leads to two different cell fates in adjacent otic precursors through lateral inhibition during the subsequent development of the auditory sensory epithelium [7,26]. Otic precursors activated by Notch signaling differentiate into supporting cells, whereas those inhibited by Notch signaling differentiate into hair cells.…”

“…JAG-1 and DLL-1 mediated the inhibition of neighboring cells to generate the hair cell/supporting cell lattice through differential temporal expression. Nevertheless, this mode may be destroyed if the signal strength of JAG-1 and DLL-1 were stimulated at the same time [26,32,38]. These results could be explained as the unique but close relationship between multiple components of the Notch signaling pathway.…”