Biology subjects

Revell, C.

Publications and source records attributed to Revell, C..

4 recordsLinked to original sources

bioRxiv2024

Apical Size Reduction by Macropinocytosis Alleviates Tissue Crowding

Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report cell size reduction via macropinocytosis as an alternative mechanism. Macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane and driving a reduction in apical cell size that remodels the epithelium to alleviate crowding. We report that this mechanism regulates the long-term organization of developing epithelium in response to proliferation-induced crowding but also serves as an immediate response to acute external compression. In both cases, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.

cell biology↗

bioRxiv2021

Notch controls the cell cycle to define leader versus follower identities during collective cell migration.

Coordination of cell proliferation and migration is fundamental for life, and its dysregulation has catastrophic consequences, 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. We propose that migratory behaviours are defined through the interaction of Notch signalling and cell cycle progression.

developmental biology↗

bioRxiv2020

Cell surface fluctuations regulate early embryonic lineage sorting

In development, lineage segregation of multiple lineages must be coordinated in time and space. An important example is the mammalian inner cell mass (ICM), in which the primitive endoderm (PrE, founder of the yolk sac) physically segregates from the epiblast (EPI, founder of the foetus). The physical mechanisms that determine this spatial segregation between EPI and PrE are still poorly understood. Here, we identify an asymmetry in cell-cell affinity, a mechanical property thought to play a significant role in tissue sorting in other systems, between EPI and PrE precursors (pEPI and pPrE). However, a computational model of cell sorting indicated that these differences alone appeared insufficient to explain the spatial segregation. We also observed significantly greater surface fluctuations in pPrE compared to pEPI. Including the enhanced surface fluctuation in pPrE in our simulation led to robust cell sorting. We identify phospho-ERM regulated membrane tension as an important mediator of the increased surface fluctuations in pPrE. Using aggregates of engineered cell lines with different surface fluctuation levels cells with higher surface fluctuations were consistently excluded to the outside of the aggregate. These cells behaved similarly when incorporated in the embryo. Surface fluctuations-driven segregation is reminiscent of activity-induced phase separation, a sorting phenomenon in colloidal physics. Together, our experiments and model identify dynamic cell surface fluctuations, in addition to static mechanical properties, as a key factor for orchestrating the correct spatial positioning of the founder embryonic lineages.

developmental biology↗

bioRxiv2018

Force-based three-dimensional model predicts mechanical drivers of cell sorting

Many biological processes, including tissue morphogenesis, are driven by mechanical sorting. However, the primary mechanical drivers of cell sorting remain controversial, in part because there remains a lack of appropriate threedimensional computational methods to probe the mechanical interactions that drive sorting. To address this important issue, we developed a three-dimensional, local force-based simulation method to enable such investigation into the sorting mechanisms of multicellular aggregates. Our method utilises the subcellular element method, in which cells are modeled as collections of locally-interacting force-bearing elements, accommodating cell growth and cell division. We define two different types of intracellular elements, assigning different attributes to boundary elements to model a cell cortex, which mediates the interfacial interaction between different cells. By tuning interfacial adhesion and tension in each cell cortex, we can control and predict the degree of sorting in cellular aggregates. The method is validated by comparing the interface areas of simulated cell doublets to experimental data and to previous theoretical work. We then define numerical measures of sorting and investigate the effects of mechanical parameters on the extent of sorting in multicellular aggregates. Using this method, we find that a minimum adhesion is required for differential interfacial tension to produce inside-out sorting of two cell types with different mechanical phenotypes. We predict the value of the minimum adhesion, which is in excellent agreement with observations in several developmental systems. We also predict the level of tension asymmetry needed for robust sorting. The generality and flexibility of the method make it applicable to tissue self-organization in a myriad of biological processes, such as tumorigenesis and embryogenesis.

biophysics↗