Matrix Rigidity Governs Switch-Like Oscillatory State Transitions of the Segmentation Clock in Isolated Presomitic Mesoderm Cells
Posted on: 18 August 2026 , updated on: 26 August 2026
Preprint posted on 16 June 2026
The clock under pressure: How presomitic mesoderm cells sense physical rigidity to control developmental timing
Selected by Felipe Del Valle Batalla
Categories: bioengineering, biophysics, cell biology, molecular biology
Background
The rhythmic formation of somites, or the building blocks of the mesoderm, during vertebrate development is controlled by the segmentation clock, a genetic circuit in the presomitic mesoderm (PSM). This circuit relies on the periodic (oscillatory) expression of genes in signalling pathways like Delta/Notch, Wnt and FGF. While the biochemical regulation of these events is well-studied, it doesn’t fully explain spatial variations in clock behaviour, such as the arrest of oscillations as cells integrate into somites.
The microenvironment of the presomitic mesoderm undergoes a rapid and major transition as cells move from the posterior to the anterior. This transition transforms the tissue from softer to stiffer. Changes in the extracellular matrix (ECM) composition and cell density suggest mechanical gradients may act as an extra layer of regulation for the clock. This preprint aims to understand how PSM cells respond to mechanical stimuli within a physiologically relevant stiffness range and how cellular physical properties like morphology and migration correlate with clock behaviour.
Key findings
Substrate stiffness acts as a genetic switch
While isolated presomitic cells functioned as self-autonomous genetic pacemakers under baseline conditions (preprint Figure 1), growing them on bioengineered substrates of varying stiffness showed a clear mechanical limit (preprint Figure 2A). The fraction of oscillating cells drops sharply above a model-predicted rigidity transition, from ~40–50% on soft surfaces to below 20% on stiffer ones. Interestingly, for cells that did keep oscillating, the clock speed stayed constant, showing those mechanical forces control whether the clock runs, not how fast it ticks (preprint Figure 2D,G).
YAP activity regulates the oscillatory state of PSM cells
Stiffer surfaces promote the translocation of the mechanosensitive protein YAP into the nucleus. Mathematical modellingf suggest that nuclear YAP acts as an inhibitor that suppresses the production rate of the clock protein Her1. The results of this study revealed a critical rigidity threshold of 3.77 kPa (preprint Figure 2F), above which YAP activity typically drove cells into a quiescent state. Chemically blocking YAP using Verteporfin increased the fraction of oscillating cells on rigid surfaces.
Oscillating cells have a distinct physical behaviour
Active, ticking cells stayed round, moved slowly, and pulled gently on their surroundings. In contrast, cells whose clocks had turned off stretched out, crawled rapidly, and pulled hard against their substrate (preprint Figure 4B, C).
Cell groups can override the mechanical shutdown
When cells formed multicellular aggregates, their communication (via Notch signalling) buffered them against mechanical constraints (preprint Figure 5). Unlike isolated single cells, these multi-cell clusters show more prominent clock oscillations across stiffness levels without experiencing a sharp mechanical shutdown.
As a summary for the results I propose the following flowchart:
Interpretation of the results as a flowchart – Rendered with ggplot2
Why I think this work is important:
This work establishes a clear link between tissue mechanics and the genetic segmentation clock. On a personal note, it also resonates with my own PhD subject which was focused on B cell mechanosensing. The methods presented in this work overcome the limitations of traditional hydrogel preparations. By isolating mechanical effects, the study offers new insights into how cell-substrate interactions regulate somitogenesis. Furthermore, identifying a rigidity threshold that aligns with the known YAP nuclear translocation threshold provides a potential molecular mechanism for how changes in the physical environment influence developmental timing.
Future directions and questions for the authors:
- While 2D assays offer precise mechanical control, they don’t fully capture the 3D confinement and tissue-scale deformations cells experience in vivo. Do the authors consider future work exploring these dynamics in more physiologically relevant 3D systems?
- The study suggests an antagonistic interaction between YAP and Notch but the specific molecular mechanisms linking these pathways to the segmentation clock’s negative feedback loop remain unclear. Could the authors share any thoughts or ideas on these mechanisms?
- The authors observed distinct oscillatory capacities in cells from different regions (anterior versus posterior PSM). A key question is how this positional information is encoded and interacts with the newly discovered mechanical gating mechanism.
doi: https://doi.org/10.1242/prelights.44472
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| List by | Virginia Savy, Martin Estermann |
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) (epi)genetics
| List by | Vibha SINGH et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
February in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry and cell metabolism 2) cell organelles and organisation 3) cell signalling, migration and mechanosensing
| List by | Barbora Knotkova et al. |
Community-driven preList – Immunology
In this community-driven preList, a group of preLighters, with expertise in different areas of immunology have worked together to create this preprint reading list.
| List by | Felipe Del Valle Batalla et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |