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Modulation of β-catenin levels is critical for cranial neural crest patterning and dispersal into first pharyngeal arch

Alok Javali, Vairavan Laxmanan, Dasaradhi Palakodeti, Ramkumar Sambasivan

Preprint posted on 9 August 2019 https://www.biorxiv.org/content/10.1101/726299v2.article-info

The kind of company you keep can have long-lasting impacts, especially in the case of developing embryos. Check out how β-catenin helps neural crest cells decide when to stick together and when to spread out.

Selected by Sruthi S Balakrishnan

Background

Neural crest cells are a special feature of vertebrate embryos. They are a transient population of cells that migrate along the developing embryo and give rise to a multitude of structures, ranging from bones to neurons. The collective migration of neural crest cells is dictated by well-timed molecular signals, interactions between cells and with extracellular elements. Any mistakes in these cues can have stark effects on the animal, such as development of a cleft lip/palate instead of a normal one1.

 

Cranial neural crest cells (CNCCs) are a subset of the neural crest that generate the cranial ganglia as well as differentiate into the skull and facial cartilage2. As the cells journey towards their intended target, it is unclear whether they stay as a collective or switch from at some point from a collective to dispersed state. Such transitions are known to occur in other cell types and the molecular determinants of such switches, which mark fate choices, are rather poorly characterised.

 

This preprint by Javali et al., provides evidence for a transition from a collective to dispersed state in CNCC. They take a closer look at molecular signals and find that β-catenin is an essential regulator of CNCC migration and patterning.

 

Summary

The authors made use of two systems to examine neural crest cell migration – one was the cranial neural crest cells (CNCCs) of mouse embryos and the other was a neural crest like cell (NCLC) line, derived from human embryonic cells. NCLCs are made by differentiating human embryonic stem cells into self-organised neurospheres, from which a migratory population starts moving out. These migratory cells express markers for neural crest cells and exhibit differential packing features characteristic of CNCCs.

 

During mouse CNCC migration, cells closer to the source (proximal) show tight packing and those further away (distal) show loose packing. This packing gradient was verified using molecular markers like N-cadherin and Fn1, which report on strength of cell adhesion and distribution of the extracellular matrix, respectively.

 

Having seen patterns in cell adhesion markers that correspond to cell packing, the researchers checked the levels of β-catenin, which is known to interact with cadherins and thereby regulate cell adhesion. In CNCCs, β-catenin is primarily seen at the plasma membrane. A key finding was that its distribution very closely matched that of N-cadherin, with the proximal cells showing more β-catenin and the distal cells displaying less β-catenin.

 

This link between β-catenin and cell patterning was further explored using pharmacological agents to either stabilise (Chiron) or destabilise (XAV) β-catenin. For these experiments, the researchers turned to the human NCLCs. When NCLCs were treated with Chiron, which stabilised β-catenin, the more distal cells were now compact and tightly packed. These cells also showed an overall increase in β-catenin and N-cadherin, implying that Chiron treatment was altering cellular distribution via the cell-cell junctions. Conversely, cells treated with XAV, which destabilised β-catenin, showed more loose patterning.

 

Now returning to the mouse CNCCs, the authors used gain-of-function β-catenin mutants, specifically in the neural crest, to test the in vivo implications of these findings. They found that in the mutants, the distal population of CNCCs was smaller than in normal embryos, with very few cells successfully reaching the pharyngeal arch. The few mutant cells that did make it, though, showed markers of fate determination. The array of mutant cells also lost the proximal to distal pattern of N-cadherin that was previously seen. Overall, stablisation of β-catenin appeared to disrupt CNCC migratory patterns and cause failure in the development of caudal arches.

 

Using both pharmacological and genetic manipulations, the authors showed a novel role for β-catenin, a known regulator of cell adhesion and migration, in controlling the migratory patterns of CNCCs.

 

What I like about this preprint

This study caught my eye for a couple of reasons, the first being that they were able to tease out a new role for β-catenin in the context of embryonic development. One would think that very little remains to be uncovered regarding elements like β-catenin and neural crest migrations, but such work shows that we never quite have the complete picture. It also highlights how different combinations of a few molecules can have numerous effects.

 

The second reason is that they used mouse embryos and cultured human NCLCs to address the same question. This not only allowed them to tackle the problem using both pharmacological reagents and genetics, but also let them draw parallels between mouse and human systems in a single setting.

 

Questions for the authors

  1. We saw that some gain-of-function β-catenin mutant cells still showed Twist1 expression if they made it to the pharyngeal arch. Does this imply that cell fate and migratory determinants work independently? How would this implication fare in the light of recent work showing that fate programs influence cellular decisions throughout the process of migration3?
  2. Previous demonstrations of β-catenin function, although Wnt-independent, have still invoked GSK-3β for its stabilisation4. Do you anticipate such modulations of β-catenin in the context of neural crest migration as well?

 

References

  1. Jones, M.C., 1990. The neurocristopathies: reinterpretation based upon the mechanism of abnormal morphogenesis. Cleft Palate Journal, 27(2), pp.136-140.
  2. Szabó, A. and Mayor, R., 2018. Mechanisms of neural crest migration. Annual review of genetics, 52, pp.43-63.
  3. Soldatov, R., Kaucka, M., Kastriti, M.E., Petersen, J., Chontorotzea, T., Englmaier, L., Akkuratova, N., Yang, Y., Häring, M., Dyachuk, V. and Bock, C., 2019. Spatiotemporal structure of cell fate decisions in murine neural crest. Science, 364(6444), p.eaas9536.
  4. Haq, S., Michael, A., Andreucci, M., Bhattacharya, K., Dotto, P., Walters, B., Woodgett, J., Kilter, H. and Force, T., 2003. Stabilization of β-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proceedings of the National Academy of Sciences, 100(8), pp.4610-4615.

Tags: development, embryo, mouse, neural crest

Posted on: 18 August 2019 , updated on: 19 August 2019

doi: https://doi.org/10.1242/prelights.13162

Read preprint (3 votes)

Author's response

Alok Javali shared

Thank you Sruthi for your interest in our work and this clear summary. Please find our response to your questions raised in the article

  • We saw that some gain-of-function β-catenin mutant cells still showed Twist1 expression if they made it to the pharyngeal arch. Does this imply that cell fate and migratory determinants work independently? How would this implication fare in the light of recent work showing that fate programs influence cellular decisions throughout the process of migration3?

We think that cell fate and migratory determinants may work in concert and such a view is in line with the recent findings (Soldatov R., et al., 2019, PMID: 31171666).

β-catenin as a player in the canonical Wnt signalling is implicated in fate choice mechanism is cranial neural crest. In this context, we interpret our findings to suggest that local cues play a key role in fate choice, in addition to β-catenin. evidence from literature suggests that Twist1 is pivotal for skeletogenic / dermogenic fate in cranial neural crest (Goodnough et al, 2016, PMID: 26677825; Soldatov R., et al., 2019, PMID: 31171666). Nevertheless, we would like to be circumspect as we have not been able to assay differentiation with lineage markers owing to early lethality of β-catenin gain-of-function mutation.

  • Previous demonstrations of β-catenin function, although Wnt-independent, have still invoked GSK-3β for its stabilisation4. Do you anticipate such modulations of β-catenin in the context of neural crest migration as well?

This is a good point. It would be interesting to test if GSK-3β inhibition by activated PKB is involved in β-catenin stabilisation in neural crest.

 

 

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