Regulation of neuronal differentiation at the neurogenic wavefront

Abstract

SUMMARYSignaling mediated by the Delta/Notch system controls the process of lateral inhibition, known to regulate neurogenesis in metazoans. Lateral inhibition takes place in equivalence groups formed by cells having equal capacity to differentiate, and it results in the singling out of precursors, which subsequently become neurons. During normal development, areas of active neurogenesis spread through non-neurogenic regions in response to specific morphogens, giving rise to neurogenic wavefronts. Close contact of these wavefronts with non-neurogenic cells is expected to affect lateral inhibition. Therefore, a mechanism should exist in these regions to prevent disturbances of the lateral inhibitory process. Focusing on the developing chick retina, we show that Dll1 is widely expressed by non-neurogenic precursors located at the periphery of this tissue, a region lacking Notch1, lFng, and differentiation-related gene expression. We investigated the role of this Dll1 expression through mathematical modeling. Our analysis predicts that the absence of Dll1 ahead of the neurogenic wavefront results in reduced robustness of the lateral inhibition process, often linked to enhanced neurogenesis and the presence of morphological alterations of the wavefront itself. These predictions are consistent with previous observations in the retina of mice in which Dll1 is conditionally mutated. The predictive capacity of our mathematical model was confirmed further by mimicking published results on the perturbation of morphogenetic furrow progression in the eye imaginal disc of Drosophila. Altogether, we propose that Notch-independent Delta expression ahead of the neurogenic wavefront is required to avoid perturbations in lateral inhibition and wavefront progression, thus optimizing the neurogenic process.

Notch-mediated lateral inhibition regulates proneural wave propagation when combined with EGF-mediated reaction diffusion

“…4E). Similar mathematical models describing the combinatorial action of Notch and a diffusible factor reproduce the patterns observed in retinal development (17)(18)(19)(20). In these studies, differentiated neurons exhibit obvious salt and pepper patterns.…”

“…Therefore, the loss of Notch signaling causes the loss of photoreceptor differentiation, which conflicts with the prediction of the above theoretical study, in which the early proneural function of Notch was not implemented (17). The previous in vivo studies using the fly retina did not specifically inhibit the later function of Notch to examine its role to suppress the wave propagation (21,22).…”

“…Although we cannot exclude this possibility, the above results suggest that the fourcomponent model with Notch-mediated lateral inhibition is essentially consistent with proneural wave progression in silico and in vivo and that the wave acceleration phenotype is equivalent to the classical neurogenic phenotype of Notch mutant clones (2). Although nonlinear regulations of Notch signaling were implemented in the previous models (5,6,(17)(18)(19), the equation for N in the four-component model was sufficient to reproduce all of the experimental conditions described above. feedback (Fig.…”

“…Previous mathematical modeling has revealed essential roles for Notch signaling in the formation of a salt and pepper pattern of photoreceptor neurons (17)(18)(19)(20). Although it was suggested that Dl restricts wave propagation during eye development (17), Notch signaling is also required for undifferentiated cells to acquire a proneural state before the wave progression in Significance Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt and pepper patterns during various developmental processes. The wave of differentiation in the Drosophila visual center accompanies Notch activity that is propagated without the formation of a salt and pepper pattern, implying that Notch does not regulate lateral inhibition during this process.…”

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].…”