Differential Robustness and Precision in Morphogen-Driven Patterning: A Dynamic Interpretation of the Hedgehog Gradient in the Drosophila Wing Disc

Core Concepts

Morphogen gradients can establish tunable patterning properties, exhibiting differential robustness and precision for different target genes.

Abstract

The article explores how morphogen gradients, specifically the Hedgehog (Hh) gradient in the Drosophila wing disc, can establish differential robustness and precision for different target genes. The key insights are: Classical steady-state models of morphogen gradient interpretation predict the same robustness for all target genes defined by different concentration thresholds. However, a dynamic interpretation of the Hh gradient, which considers the transient "overshoot" and the steady-state gradient, reveals that targets defined by the overshoot are less robust to changes in morphogen dosage compared to those defined by the steady-state gradient. This reduced robustness of overshoot-defined targets (e.g., dpp) is compensated by increased precision in their patterning, compared to steady-state-defined targets (e.g., col). The differential robustness is enabled by the Hh-dependent upregulation of its own receptor Patched, which provides robustness to steady-state-defined targets but has little effect on overshoot-defined targets. Experimental validation confirms the model predictions, showing that the col pattern is more robust to changes in Hh dosage compared to the dpp pattern, and that the robustness of col depends on Hh-dependent Patched upregulation. The work reveals how a single morphogen gradient can be interpreted dynamically to tune the robustness and precision properties of different target genes, providing a flexible patterning strategy.

Stats

The width of the col pattern is reduced by 1.64 μm in hh heterozygous discs compared to wild-type. The width of the dpp pattern is reduced by 5.56 μm in hh heterozygous discs compared to wild-type. The difference in the width of the col pattern between 18°C and 25-29°C in ptc-/-; TPT/hhts2 discs is 4.57 μm.

Quotes

"Hh-dependent Ptc upregulation acts as a negative feedback that plays important roles in self-limiting the range of the gradient (Chen and Struhl, 1996; Briscoe et al., 2001), desensitizing signal exposure over time (Dessaud et al., 2008), and controlling the spatial dynamics of the gradient (Nahmad and Stathopoulos, 2009)." "While having dpp respond to the steady-state, rather than the overshoot behavior of the Hh gradient, could have conferred on dpp the same robustness to Hh dosage as Col, it would have come at a cost. This is because self-enhanced ligand-degradation gradients dramatically lose precision several lengthscales away from the source. By interpreting the dpp pattern using the overshoot of the Hh gradient, loss of robustness is offset by gains in precision, allowing the dpp stripe to be sharper than would have been the case otherwise."

Key Insights Distilled From

Dynamic readout of the Hh gradient in the Drosophila wing disc reveals pattern-specific tradeoffs between robustness and precision

by Reyes,R., La... at www.biorxiv.org 12-22-2022

https://www.biorxiv.org/content/10.1101/2022.12.21.521489v1

Deeper Inquiries

How might this differential robustness and precision strategy be employed in other developmental patterning systems beyond the Drosophila wing disc?

In other developmental systems, the differential robustness and precision strategy observed in the Drosophila wing disc could be employed to fine-tune the patterning of various tissues and organs. For example, in vertebrate limb development, where morphogen gradients play a crucial role in specifying digit identity, this strategy could ensure the robust establishment of key features like digit boundaries while allowing for more precise positioning of individual digits. Additionally, in neural tube patterning, differential robustness and precision could help establish distinct neural cell types with specific spatial arrangements, ensuring the reproducibility of neural circuits while allowing for subtle variations in neuronal connectivity.

What other mechanisms, beyond Hh-dependent Patched upregulation, could provide robustness to morphogen-driven patterning outputs?

Several other mechanisms could contribute to robustness in morphogen-driven patterning outputs. One such mechanism is feedback regulation, where downstream targets of the morphogen pathway regulate the expression or activity of components in the pathway itself. This feedback loop can help maintain the stability and fidelity of the morphogen gradient by adjusting the levels of signaling components in response to changes in morphogen concentration. Additionally, post-translational modifications, such as protein degradation or phosphorylation, can act as buffering mechanisms to dampen fluctuations in morphogen levels and ensure consistent patterning outcomes. Furthermore, the presence of redundant signaling pathways or cross-talk between different signaling cascades can provide backup mechanisms to compensate for variations in morphogen signaling, enhancing the robustness of patterning outputs.

How do the tradeoffs between robustness and precision in morphogen gradient interpretation relate to the evolutionary adaptability and evolvability of developmental systems?

The tradeoffs between robustness and precision in morphogen gradient interpretation play a crucial role in the evolutionary adaptability and evolvability of developmental systems. While robustness ensures the reproducibility and stability of patterning outcomes in the face of genetic or environmental perturbations, precision allows for fine-tuning and subtle variations in developmental processes, enabling the generation of diverse phenotypes. Evolutionary pressures may favor certain tradeoffs between robustness and precision depending on the specific developmental context. For example, in highly conserved developmental processes where precise patterning is essential for organismal viability, robustness may be prioritized to ensure the reliable formation of critical structures. On the other hand, in systems where flexibility and adaptability are advantageous, precision may be favored to allow for the generation of novel phenotypes in response to changing environmental conditions or selective pressures. Overall, the dynamic interplay between robustness and precision in morphogen gradient interpretation provides developmental systems with the necessary flexibility to adapt to changing evolutionary demands while maintaining the stability and reproducibility of essential patterning processes.