Notch controls the cell cycle to define leader versus follower identities during collective cell migration
Abstract
Coordination of cell proliferation and migration is fundamental for life, and its dysregulation has catastrophic consequences, such as cancer. How cell cycle progression affects migration, and vice-versa, remains largely unknown. We address these questions by combining in-silico modelling and in vivo experimentation in the zebrafish Trunk Neural Crest (TNC). TNC migrate collectively, forming chains with a leader cell directing the movement of trailing followers. We show that the acquisition of migratory identity is autonomously controlled by Notch signalling in TNC. High Notch activity defines leaders, while low Notch determines followers. Moreover, cell cycle progression is required for TNC migration and is regulated by Notch. Cells with low Notch activity stay longer in G1 and become followers, while leaders with high Notch activity quickly undergo G1/S transition and remain in S-phase longer. In conclusion, TNC migratory identities are defined through the interaction of Notch signalling and cell cycle progression.
Data availability
The model code is accessible at https://github.com/Bentley-Cellular-Adaptive-Behaviour-Lab/NeuralCrestCpp. The code used to perform the LDA analysis is accessible in the supplementary files. All numerical data used in the figures is accessible in the supplementary data source file.
Article and author information
Author details
Funding
Medical Research Council (G1000080/1)
- Zain Alhashem
Royal Society (2010/R1)
- Zain Alhashem
Wellcome Trust (207630/Z/17/Z)
- Zain Alhashem
Eucine Kennedy Shiver National Institute of Child Health & Human Development of the National Institues of Health (T32HD055164)
- Manuel Rocha
Eucine Kennedy Shiver National Institute of Child Health & Human Development of the National Institues of Health (F31HD097957)
- Manuel Rocha
Cancer Research UK (FC001751)
- Dylan Feldner-Busztin
Medical Research Council (FC001751)
- Dylan Feldner-Busztin
Wellcome Trust (FC001751)
- Dylan Feldner-Busztin
Biotechnology and Biological Sciences Research Council (BB/S015906/1)
- Robert Kelsh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tatjana Piotrowski, Stowers Institute for Medical Research, United States
Ethics
Animal experimentation: Zebrafish were maintained in accordance with UK Home Office regulations UK Animals (Scientific Procedures) Act 1986, amended in 2013 under project license P70880F4C.
Version history
- Preprint posted: May 27, 2021 (view preprint)
- Received: September 7, 2021
- Accepted: March 22, 2022
- Accepted Manuscript published: April 19, 2022 (version 1)
- Version of Record published: May 24, 2022 (version 2)
Copyright
© 2022, Alhashem et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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Large-scale cell flow characterizes gastrulation in animal development. In amniote gastrulation, particularly in avian gastrula, a bilateral vortex-like counter-rotating cell flow, called ‘polonaise movements’, appears along the midline. Here, through experimental manipulations, we addressed relationships between the polonaise movements and morphogenesis of the primitive streak, the earliest midline structure in amniotes. Suppression of the Wnt/planar cell polarity (PCP) signaling pathway maintains the polonaise movements along a deformed primitive streak. Mitotic arrest leads to diminished extension and development of the primitive streak and maintains the early phase of the polonaise movements. Ectopically induced Vg1, an axis-inducing morphogen, generates the polonaise movements, aligned to the induced midline, but disturbs the stereotypical cell flow pattern at the authentic midline. Despite the altered cell flow, induction and extension of the primitive streak are preserved along both authentic and induced midlines. Finally, we show that ectopic axis-inducing morphogen, Vg1, is capable of initiating the polonaise movements without concomitant PS extension under mitotic arrest conditions. These results are consistent with a model wherein primitive streak morphogenesis is required for the maintenance of the polonaise movements, but the polonaise movements are not necessarily responsible for primitive streak morphogenesis. Our data describe a previously undefined relationship between the large-scale cell flow and midline morphogenesis in gastrulation.
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Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.