ERK-Mediated Mechanochemical Waves Direct Collective Cell Polarization

Hino, Naoko; Rossetti, Leone; Marín-Llauradó, Ariadna; Aoki, Kazuhiro; Trepat, Xavier; Matsuda, Minoru; Hirashima, Tsuyoshi

doi:10.1016/j.devcel.2020.05.011

Cited by 201 publications

(235 citation statements)

References 84 publications

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“…Activation of ERK signaling and consequential enhancement of induced neuronal differentiation has also been reported upon the downregulation of the ERK-inhibitor Spry4 in PC12 cells (Alsina et al, 2012 ) and upon increased interaction with the neural cell adhesion molecule NCAM in SH-SY5Y cells (Seidenfaden et al, 2006 ). Contrary to our observation that activation of ERK in Willin/FRMD6 knockdown cells resulted in reduced cell force exertion, ERK has been reported to trigger cell contractility in a non-neuronal cell type (Hino et al, 2020 ).…”

Section: Discussioncontrasting

confidence: 99%

Willin/FRMD6 Influences Mechanical Phenotype and Neuronal Differentiation in Mammalian Cells by Regulating ERK1/2 Activity

Kronenberg

Tilston-Lünel

Thompson

et al. 2020

Front. Cell. Neurosci.

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Willin/FRMD6 is part of a family of proteins with a 4.1 ezrin-radixin-moesin (FERM) domain. It has been identified as an upstream activator of the Hippo pathway and, when aberrant in its expression, is associated with human diseases and disorders. Even though Willin/FRMD6 was originally discovered in the rat sciatic nerve, most studies have focused on its functional roles in cells outside of the nervous system, where Willin/FRMD6 is involved in the formation of apical junctional cell-cell complexes and in regulating cell migration. Here, we investigate the biochemical and biophysical role of Willin/FRMD6 in neuronal cells, employing the commonly used SH-SY5Y neuronal model cell system and combining biochemical measurements with Elastic Resonator Interference Stress Micropscopy (ERISM). We present the first direct evidence that Willin/FRMD6 expression influences both the cell mechanical phenotype and neuronal differentiation. By investigating cells with increased and decreased Willin/FRMD6 expression levels, we show that Willin/FRMD6 not only affects proliferation and migration capacity of cells but also leads to changes in cell morphology and an enhanced formation of neurite-like membrane extensions. These changes were accompanied by alterations of biophysical parameters such as cell force, the organization of actin stress fibers and the formation of focal adhesions. At the biochemical level, changes in Willin/FRMD6 expression inversely affected the activity of the extracellular signal-regulated kinases (ERK) pathway and downstream transcriptional factor NeuroD1, which seems to prime SH-SY5Y cells for retinoic acid (RA)-induced neuronal differentiation.

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Section: Discussioncontrasting

confidence: 99%

Willin/FRMD6 Influences Mechanical Phenotype and Neuronal Differentiation in Mammalian Cells by Regulating ERK1/2 Activity

Kronenberg

Tilston-Lünel

Thompson

et al. 2020

Front. Cell. Neurosci.

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“…Thus, DVM predicts a dominant role for propulsion during UJT. Indeed, previous experimental work has linked traction forces, propulsion, and collective epithelial migration 115 , which has been further shown to require ERK activation 97,116 . ERK activation, which is required for compression-induced UJT ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

In primary airway epithelial cells, the unjamming transition is distinct from the epithelial-to-mesenchymal transition

et al. 2020

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The epithelial-to-mesenchymal transition (EMT) and the unjamming transition (UJT) each comprises a gateway to cellular migration, plasticity and remodeling, but the extent to which these core programs are distinct, overlapping, or identical has remained undefined. Here, we triggered partial EMT (pEMT) or UJT in differentiated primary human bronchial epithelial cells. After triggering UJT, cell-cell junctions, apico-basal polarity, and barrier function remain intact, cells elongate and align into cooperative migratory packs, and mesenchymal markers of EMT remain unapparent. After triggering pEMT these and other metrics of UJT versus pEMT diverge. A computational model attributes effects of pEMT mainly to diminished junctional tension but attributes those of UJT mainly to augmented cellular propulsion. Through the actions of UJT and pEMT working independently, sequentially, or interactively, those tissues that are subject to development, injury, or disease become endowed with rich mechanisms for cellular migration, plasticity, self-repair, and regeneration.

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“…measured no metabolic indices, they reported that creation of a free space launches not only an advancing wave of migration, which acts to fill that free space and thus heal the wound, but also a retrograde wave of unjamming that acts to mobilize cells in the ranks behind and thereby recruit them to the advancing front 29 , 32 , 33 . In this unjamming process retrograde waves of cell deformation trigger retrograde waves of ERK activation in a sustained mechano-chemical feedback loop 34 . These changes in mechanical, chemical, and morphological indices spatially coincide with the regions in the epithelial cell layer where the redox ratio is dramatically reduced (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epithelial layer unjamming shifts energy metabolism toward glycolysis

DeCamp

Tsuda

Ferruzzi

et al. 2020

Sci Rep

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In development of an embryo, healing of a wound, or progression of a carcinoma, a requisite event is collective epithelial cellular migration. For example, cells at the advancing front of a wound edge tend to migrate collectively, elongate substantially, and exert tractions more forcefully compared with cells many ranks behind. With regards to energy metabolism, striking spatial gradients have recently been reported in the wounded epithelium, as well as in the tumor, but within the wounded cell layer little is known about the link between mechanical events and underlying energy metabolism. Using the advancing confluent monolayer of MDCKII cells as a model system, here we report at single cell resolution the evolving spatiotemporal fields of cell migration speeds, cell shapes, and traction forces measured simultaneously with fields of multiple indices of cellular energy metabolism. Compared with the epithelial layer that is unwounded, which is non-migratory, solid-like and jammed, the leading edge of the advancing cell layer is shown to become progressively more migratory, fluid-like, and unjammed. In doing so the cytoplasmic redox ratio becomes progressively smaller, the NADH lifetime becomes progressively shorter, and the mitochondrial membrane potential and glucose uptake become progressively larger. These observations indicate that a metabolic shift toward glycolysis accompanies collective cellular migration but show, further, that this shift occurs throughout the cell layer, even in regions where associated changes in cell shapes, traction forces, and migration velocities have yet to penetrate. In characterizing the wound healing process these morphological, mechanical, and metabolic observations, taken on a cell-by-cell basis, comprise the most comprehensive set of biophysical data yet reported. Together, these data suggest the novel hypothesis that the unjammed phase evolved to accommodate fluid-like migratory dynamics during episodes of tissue wound healing, development, and plasticity, but is more energetically expensive compared with the jammed phase, which evolved to maintain a solid-like non-migratory state that is more energetically economical.

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ERK-Mediated Mechanochemical Waves Direct Collective Cell Polarization

Cited by 201 publications

References 84 publications

Willin/FRMD6 Influences Mechanical Phenotype and Neuronal Differentiation in Mammalian Cells by Regulating ERK1/2 Activity

Willin/FRMD6 Influences Mechanical Phenotype and Neuronal Differentiation in Mammalian Cells by Regulating ERK1/2 Activity

In primary airway epithelial cells, the unjamming transition is distinct from the epithelial-to-mesenchymal transition

Epithelial layer unjamming shifts energy metabolism toward glycolysis

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