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Dynamics of Proneural Gene Expression and Cell Fate Decisions During Lateral Inhibition in the Drosophila Pupal Abdomen

Core Concepts
Fate symmetry breaking during lateral inhibition occurs at low levels of the proneural factor Scute, and cell-to-cell variations in Scute levels promote rapid fate divergence.
The authors used live imaging and quantitative analysis to study the dynamics of the proneural factor Scute (Sc) during lateral inhibition in the developing Drosophila pupal abdomen. They found that: Fate symmetry breaking, where cells adopt distinct fates, occurred at low levels of Sc expression, without a prolonged phase of mutual inhibition. Cell-to-cell variations in Sc levels increased prior to fate symmetry breaking and positively correlated with the rate of fate divergence. Experimentally increasing Sc heterogeneity led to faster fate decisions. Notch activity was minimal around the time of fate symmetry breaking, suggesting that Notch-mediated lateral inhibition acts rapidly at low proneural levels to generate the salt-and-pepper pattern of sensory organ precursor (SOP) cells. In a small fraction of cases (~10%), pairs of neighboring cells adopted the SOP fate, but these defects were corrected through subsequent cell rearrangements. Overall, the study provides insights into the spatial and temporal dynamics of lateral inhibition, showing that initial differences in proneural gene expression are amplified to generate stable cell fates, and that cell-to-cell heterogeneity plays a key role in promoting rapid fate divergence.
The mean number of apical neighbors for SOPs was 5.8 ± 1.1 (n=35). The half-life of the destabilized GFP (deGFP) reporter used to monitor Notch activity was ~2 hours.
"Fate symmetry breaking occurred at low Sc levels and that fate divergence was not preceded by a prolonged phase of low or intermediate level of Sc accumulation." "Cell-to-cell variations in Sc levels promoted fate divergence, thereby providing experimental support for the intercellular negative feedback loop model." "Lateral inhibition appeared to act early and fast, at low levels of proneural and Notch activities, in this tissue."

Deeper Inquiries

How do initial differences in proneural gene expression arise in the proneural field prior to fate symmetry breaking

In the context of the pupal abdomen in Drosophila, initial differences in proneural gene expression in the proneural field prior to fate symmetry breaking can arise through various mechanisms. One key factor contributing to these initial differences is likely the inherent stochasticity in gene expression. Proneural genes, such as Ac and Sc, are known to be expressed in a stochastic manner within proneural clusters. This stochastic expression can lead to subtle variations in the levels of proneural factors among neighboring cells, even when they are initially equipotent. These small differences in gene expression can serve as the basis for the amplification of random fluctuations in Notch and proneural activity, ultimately leading to ordered patterns of cell fates through lateral inhibition. Additionally, the presence of spatial cues or gradients within the tissue can also influence the initial differences in proneural gene expression. For example, in the pupal abdomen, posterior cues have been shown to regulate early proneural gene expression in the ADHN. These cues may create a spatial bias in the distribution of proneural factors, contributing to the asymmetry in gene expression within the proneural field. Furthermore, interactions between neighboring cells, such as cell-cell signaling or mechanical forces, can further modulate proneural gene expression and introduce variability in the levels of proneural factors among cells in the proneural cluster. Overall, the combination of stochastic gene expression, spatial cues, and cell-cell interactions likely contributes to the emergence of initial differences in proneural gene expression in the proneural field prior to fate symmetry breaking during lateral inhibition.

What are the potential mechanisms that could lead to the formation of SOP twins that are in direct contact at the time of fate specification

The formation of SOP twins that are in direct contact at the time of fate specification can be attributed to several potential mechanisms in the context of lateral inhibition in Drosophila. One possible mechanism is related to the dynamics of Notch signaling and its role in cell fate determination. In cases where pairs of SOPs emerge in close proximity, it is possible that the inhibitory signals mediated by Notch between neighboring cells are not effectively transmitted or received, leading to a failure in the lateral inhibition process. This could result from variations in Notch activity levels or disruptions in the Notch-mediated feedback loop that regulates cell fate decisions. Another potential mechanism could involve defects in cell-cell adhesion or changes in cell adhesion properties. Cell rearrangements and movements during development could lead to the physical proximity of SOPs, overriding the inhibitory signals that should prevent the selection of multiple SOPs in close proximity. Additionally, alterations in the expression of adhesion molecules or changes in the mechanical properties of cells could impact the spatial organization of cells within the proneural cluster, contributing to the formation of SOP twins. Furthermore, the presence of genetic mutations or environmental factors that disrupt the normal signaling pathways involved in lateral inhibition could also lead to the occurrence of SOP twins. These factors may interfere with the precise regulation of cell fate decisions, resulting in patterning defects and the emergence of multiple SOPs in direct contact at the time of fate specification.

How do the dynamics of lateral inhibition and cell fate patterning differ in other developmental contexts, such as the pupal notum, and what factors might contribute to these differences

The dynamics of lateral inhibition and cell fate patterning can vary in different developmental contexts, such as the pupal notum, compared to the pupal abdomen in Drosophila. One key difference lies in the spatial and temporal regulation of proneural gene expression and Notch signaling. In the pupal notum, the dynamics of proneural gene expression and Notch activity may be influenced by distinct spatial cues or signaling gradients, leading to unique patterns of cell fate specification. Additionally, the cellular environment and interactions within the pupal notum may differ from those in the abdomen, affecting the efficiency and precision of lateral inhibition. Moreover, the genetic and molecular components involved in lateral inhibition and fate determination may vary between different tissues, contributing to differences in the dynamics of cell fate patterning. For example, the expression levels of proneural factors, the activity of Notch signaling components, and the feedback mechanisms regulating fate decisions may be context-dependent and result in diverse outcomes in terms of cell fate specification. Furthermore, the presence of tissue-specific factors or regulatory networks could also play a role in shaping the dynamics of lateral inhibition in different developmental contexts. These factors may modulate the sensitivity of cells to inhibitory signals, the speed of fate divergence, or the robustness of the patterning process, leading to variations in the outcomes of cell fate decisions. Overall, the interplay between tissue-specific factors, spatial cues, and genetic regulatory networks contributes to the diversity of cell fate patterning dynamics observed in different developmental contexts.