Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear

Abstract

During inner ear development, Notch exhibits two modes of operation: lateral induction, which is associated with prosensory specification, and lateral inhibition, which is involved in hair cell determination. These mechanisms depend respectively on two different ligands, jagged 1 (Jag1) and delta 1 (Dl1), that rely on a common signaling cascade initiated after Notch activation. In the chicken otocyst, expression of Jag1 and the Notch target Hey1 correlates well with lateral induction, whereas both Jag1 and Dl1 are expressed during lateral inhibition, as are Notch targets Hey1 and Hes5. Here, we show that Jag1 drives lower levels of Notch activity than Dl1, which results in the differential expression of Hey1 and Hes5. In addition, Jag1 interferes with the ability of Dl1 to elicit high levels of Notch activity. Modeling the sensory epithelium when the two ligands are expressed together shows that ligand regulation, differential signaling strength and ligand competition are crucial to allow the two modes of operation and for establishing the alternate pattern of hair cells and supporting cells. Jag1, while driving lateral induction on its own, facilitates patterning by lateral inhibition in the presence of Dl1. This novel behavior emerges from Jag1 acting as a competitive inhibitor of Dl1 for Notch signaling. Both modeling and experiments show that hair cell patterning is very robust. The model suggests that autoactivation of proneural factor Atoh1, upstream of Dl1, is a fundamental component for robustness. The results stress the importance of the levels of Notch signaling and ligand competition for Notch function.

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

“…Here, we introduced a specially designed theoretical framework to study Notch signaling through both Delta and Jagged which incorporates the effect of the asymmetries between these two key ligands. An earlier attempt included both Delta and Jagged in Notch signaling system (9). Although it explains some of their own experimental results, it does not include some fundamental features of Notch signaling, such as cis-inhibition between Notch and Delta (14), cis-inhibition between Notch and Jagged (37), and the effect of glycosyltransferase Fringe that causes an asymmetry between Notch-Delta and Notch-Jagged signaling (34,35).…”

“…Therefore, both cells can act as both Receiver (R) and Sender (S)--or the two cells acquire similar fates. This mechanism, known as lateral induction, is implicated, for example, in mammalian inner-ear development (8,9), control of epidermal stem cell clusters (10), as well as inner cardiac development (11). Therefore, Delta and Jagged affect the collective cell-fate decisions in a group of cells quite differently.…”

Tópicos em sinalização celular e bioinformática: Princípios de funcionamento do circuito de sinalização Notch e aprendizagem supervisionada variacional de relevância

“…This model brings interesting insights about patterning formation by Notch-Delta signaling circuit and many extensions of this model have been developed over the past years [12,39,40,41]. One particularly interesting extension of Collier's model was proposed by Petrovic et al [12].…”

“…One particularly interesting extension of Collier's model was proposed by Petrovic et al [12]. Their model was the first framework to include both ligands Delta and Jagged, and their simulations was useful to understand some of their experimental results in the context of inner ear development [12].…”

“…On the other hand, two cells interacting via Notch-Jagged can act as both Sender and Receiver as they have (high Jagged (ligand), high Notch (receptor)) on their surface. This cell-fate convergence mechanism is known as lateral induction ( Figure 1C) and is crucial during cardiac development, inner ear development, and the formation of a smooth muscle wall around a nascent artery [11,12,13,14].…”