Specified Neural Progenitors Sort to Form Sharp Domains after Noisy Shh Signaling

Abstract

SUMMARY Sharply delineated domains of cell types arise in developing tissues under the instruction of inductive signal (morphogen) gradients, which specify distinct cell fates at different signal levels. The translation of a morphogen gradient into discrete spatial domains relies on precise signal responses at stable cell positions. However, cells in developing tissues undergoing morphogenesis and proliferation often experience complex movements, which may affect their morphogen exposure, specification, and positioning. How is a clear pattern achieved with cells moving around? Using in toto imaging of the zebrafish neural tube, we analyzed specification patterns and movement trajectories of neural progenitors. We found that specified progenitors of different fates are spatially mixed following heterogeneous Sonic Hedgehog signaling responses. Cell sorting then rearranges them into sharply bordered domains. Ectopically induced motorneuron progenitors also robustly sort to correct locations. Our results reveal that cell sorting acts to correct imprecision of spatial patterning by noisy inductive signals.

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

“…These migratory events lead to clustering and positioning of neural progenitors to establish discrete boundaries between domains (Xiong et al, 2013). Strikingly, ectopic motoneurons induced in the zebrafish neural tube migrate into the appropriate region independent of their initial position (Xiong et al, 2013). Conservation of this mechanism in mice would predict that ectopic ventral progenitors in embryos with disrupted LDA should migrate into their appropriate positions and produce discrete boundaries.…”

“…Alternatively, the ectopic progenitors in LDA mutants could have been specified after cells are epithelialized and are therefore unable to migrate. One intriguing possibility is that the proper regulation of HH ligands is required to direct these coordinated cell movements, despite an apparent lack of a role for downstream signaling in this process (Xiong et al, 2013).…”

A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity

“…At the tissue scale, defining robust strategies of self-organization is critical for engineering functional tissues, as well as for understanding development and the breakdown of tissue structure during diseases such as cancer (1). During development, two or more populations of motile cells can self-organize into spatially ordered tissues by a process referred to as cell sorting (2)(3)(4). The outcome of cell sorting can be rationalized using physical models that invoke cell-type-specific differences in interfacial energies.…”

Spatiotemporal Analysis of Different Mechanisms for Interpreting Morphogen Gradients

“…Although it would be interesting to include these effects in our analysis, they are unlikely to alter our general conclusions about the relative benefits of measuring concentration versus its derivatives. We have also not considered the role that cell movement can play in sharpening boundaries (46). Furthermore, with increased quality of experimental data, it is becoming increasingly clear that many morphogen gradients do not form via a simple SDD mechanism (41)(42)(43)80,81).…”

“…Reliable interpretation of the morphogen signal is essential for precise spatial positioning (45), and experimental evidence now suggests that the French Flag model alone is insufficient to explain the observed boundary specification (14,46,47). For example, there is increasing evidence that many morphogen gradients may actually be interpreted before steady state (22,(48)(49)(50)(51)(52).…”