Heterogeneity in Sonic Hedgehog Response Dynamics and Fate Specification of Single Neural Progenitors

핵심 개념

Single neural progenitors exhibit significant heterogeneity in their Sonic hedgehog response dynamics, which is not fully predictive of their eventual fate choices.

초록

The study investigates the relationship between Sonic hedgehog (Shh) signaling response and fate specification in single neural progenitor cells in the developing zebrafish neural tube. Using live imaging and quantitative analysis, the authors made the following key observations:

There is significant heterogeneity in Shh response dynamics between single cells, even among those that eventually adopt the same fate. Cells with similar Shh responses can make different fate choices, and cells with distinct Shh responses can adopt the same fate.

The authors quantified different metrics of Shh response, such as maximum transient level, response time, and average response level, and evaluated how well they correlate with fate outcomes. They found that in the anterior neural tube, all these metrics are highly predictive of fate choice (>85% correlation). However, in the posterior neural tube, only the maximum transient Shh response level remains a good predictor (>80% correlation), while the other metrics fail to make accurate predictions.

The authors suggest that the heterogeneity in Shh response-fate correlation, particularly in the posterior neural tube, may be due to differences in tissue geometry, cell movement, and morphogen source along the anterior-posterior axis. This introduces additional noise and variability in morphogen interpretation that cannot be fully accounted for by simple response-fate models.

The results highlight the precision limits of morphogen-interpretation gene regulatory networks in small and dynamic target cell fields, where factors beyond the morphogen gradient, such as cell position, movement, and noise, play important roles in fate specification.

통계

The maximum transient Shh response level is >80% correlated with fate choice in the posterior neural tube.
The average Shh response level and response time are >85% correlated with fate choice in the anterior neural tube.

인용구

"Strikingly, at the single cell level, we observed high variability in Shh-signaling reporter dynamics across cells of the same fate and some overlap of cells that finally take on different fates."
"For the anterior tracks, the LMDV distance is consistently >90% correlated while for the posterior tracks the LMDV distance is more poorly correlated at earlier stages but becomes better at later times consistent with a necessary role for cell sorting in sharpening fate domain boundaries over time."

핵심 통찰 요약

Heterogeneity of Sonic Hedgehog response dynamics and fate specification in single neural progenitors

by Xiong,F., Te... 게시일 www.biorxiv.org 09-10-2018

https://www.biorxiv.org/content/10.1101/412858v2

더 깊은 질문

How do other signaling pathways, such as Notch, interact with the Shh signaling network to influence fate specification and introduce additional heterogeneity at the single cell level

Other signaling pathways, such as Notch, play a crucial role in interacting with the Sonic hedgehog (Shh) signaling network to influence fate specification and introduce additional heterogeneity at the single cell level. Notch signaling is known to crosstalk with Shh signaling in various developmental processes, including neural tube patterning. In the context of the neural tube, Notch signaling can modulate the response of neural progenitors to Shh gradients, affecting their fate decisions.
Specifically, Notch signaling can regulate the expression of key transcription factors and downstream effectors that are involved in neural progenitor fate specification. This interaction can lead to variations in the interpretation of the Shh gradient by individual cells, resulting in heterogeneity in fate choices. Notch signaling can influence the expression of genes that are part of the genetic regulatory network (GRN) downstream of Shh, potentially altering the threshold levels, duration of response, or integration of Shh signaling inputs in a cell-specific manner.
Furthermore, Notch signaling can also impact cell-cell interactions and lateral inhibition mechanisms, which are essential for refining cell fate decisions in response to morphogen gradients. By modulating the expression of Notch ligands and receptors, cells can communicate with their neighbors and adjust their fate choices based on local signaling cues. This interplay between Notch and Shh signaling pathways adds another layer of complexity to the fate specification process, contributing to the heterogeneity observed at the single cell level.

What are the specific molecular mechanisms and gene regulatory network dynamics that underlie the differences in Shh response-fate correlation between the anterior and posterior neural tube regions

The differences in Shh response-fate correlation between the anterior and posterior neural tube regions can be attributed to specific molecular mechanisms and gene regulatory network dynamics that operate in a region-specific manner. In the anterior neural tube, where the tissue geometry and cell movements differ from the posterior region, the correlation between Shh response dynamics and fate choices is more pronounced. This could be due to the presence of additional signaling inputs or regulatory factors that fine-tune the interpretation of the Shh gradient in a more predictable manner.
In contrast, the posterior neural tube exhibits a higher degree of noise and variability in the Shh response-fate correlation. This could be influenced by factors such as cell mixing, tissue size, and morphogen source differences that introduce more positional noise in signaling. The tissue geometry and cell dynamics in the posterior region may create a less stable environment for precise morphogen interpretation, leading to the observed heterogeneity in fate choices at the single cell level.
At the molecular level, differences in the expression of signaling components, transcription factors, or feedback mechanisms between the anterior and posterior regions could contribute to the distinct Shh response profiles and fate outcomes. The timing of response initiation, the duration of response, and the peak levels of Shh signaling activity may vary between the two regions, leading to differential fate specification patterns. Understanding these region-specific molecular mechanisms and regulatory dynamics is essential for elucidating the differences in Shh response-fate correlation observed in the neural tube.

How do the findings from this study on morphogen interpretation in the developing neural tube apply to other morphogen-patterned tissues, and what are the general principles for achieving robust pattern formation despite inherent cellular heterogeneity

The findings from this study on morphogen interpretation in the developing neural tube have broader implications for understanding pattern formation in other morphogen-patterned tissues. The general principles for achieving robust pattern formation despite inherent cellular heterogeneity can be applied to various developmental contexts where morphogens play a critical role in specifying cell fates and tissue organization.
One key principle is the concept of averaging out heterogeneity at the population level to maintain pattern precision. While single cells may exhibit variability in their response to morphogen gradients, the collective behavior of a population of cells can lead to the establishment of stable and reproducible patterns. This population-level robustness can buffer against noise and fluctuations at the single cell level, ensuring the fidelity of pattern formation.
Additionally, the role of additional signaling pathways, cell-cell interactions, and feedback mechanisms in refining fate decisions and sharpening pattern boundaries is crucial for achieving precise morphogen interpretation. By integrating multiple signaling inputs and regulatory networks, cells can coordinate their responses to morphogens and adjust their fate choices based on environmental cues and positional information.
Overall, the study highlights the complexity of morphogen interpretation and fate specification in developing tissues and underscores the importance of understanding the interplay between signaling pathways, gene regulatory networks, and cellular dynamics in achieving robust and precise pattern formation. These principles can be extrapolated to diverse morphogen-driven processes in development, providing insights into the mechanisms that govern tissue patterning and cell fate determination.