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Developmental Biology - Cell Adhesion

Pressure Induces Cells to Get Sticky

In the first two weeks of embryo development, 'force' changes cell surface tension — essential in organ formation...

From Japan's National Institute for Basic Biology (NIBB) doctors Noriyuki Kinoshita and Naoto Ueno, along with Ileana Cristea MD from Princeton University, have demonstrated how physical force (centrifuge type force) enhances cell-to-cell stickyness.

Cells sticking to cells increases their stiffness and likelihood of becomming the walls that define tissues. Force from the ever increasing interior pressure of expanding cells, pushes against this exterior cellular stiffening. Scientists studying this transitional period in embryo cell growth, also identified which signaling pathways are the foundation of this changable phenomenon. They reveal that physical force triggers all cell wall stiffening and provides for the continued development of the embryo.

Their work was published on March 12, 2020 in Cell Reports.
It is increasingly recognized that genes and proteins, are affected by physical forces as components of living organisms. These forces reflect normal development while simultaneously maintaining homeostasis.
This research has deepened an existing collaboration between NIBB and Princeton University, and led to a joint article published in 2019 (Cell Systems), investigating force-dependent cellular events. In that previous research, it was demonstrated how a sizable number of proteins in embryonic tissues become phosphorylated, immediately after compression force is applied. The ZO-1 tight junction protein accumulates at junctions, leading to enhancement of cell-to-cell contact bridging those junctions.
The authors found that Erk2, an important signaling component, mediated various external stimuli to become phosphorylated by those forces and translocate into the nucleus. They also confirmed that inhibiting Erk2 phosphorylation, reduced force and the subsequent stiffening of tissues. Thus demonstrating that Erk2 is essential for force-induced cell remodeling.
The group also noted how Erk2 phosphorylation is triggered upon receiving a signal through the FGF Receptor (fibroblast growth factor receptor). So they propose that FGFR is activated by forces in the absence of the FGF ligand. In unique opposition to conventional FGFR activation by its ligand.
These results suggest activation of FGFR is triggered by force induced cell deformation — or shape change. This is a significant step towards addressing the long-standing question of how physical forces influence cell and tissue behaviors.
Abstract Highlights

• Mechanical force induces phosphorylation of cell junction components

• Kinase profile of mechanoresponses revealed rapid activation of basophilic kinases

• The focal adhesion kinase induces PKC activity during mechanoresponse in Xenopus

• Centrifugation force induces MET-like phenotype

Summary
Mechanical forces are essential drivers of numerous biological processes, notably during development. Although it is well recognized that cells sense and adapt to mechanical forces, the signal transduction pathways that underlie mechanosensing have remained elusive. Here, we investigate the impact of mechanical centrifugation force on phosphorylation-mediated signaling in Xenopus embryos. By monitoring temporal phosphoproteome and proteome alterations in response to force, we discover and validate elevated phosphorylation on focal adhesion and tight junction components, leading to several mechanistic insights into mechanosensing and tissue restoration. First, we determine changes in kinase activity profiles during mechanoresponse, identifying the activation of basophilic kinases. Pathway interrogation using kinase inhibitor treatment uncovers a crosstalk between the focal adhesion kinase (FAK) and protein kinase C (PKC) in mechanoresponse. Second, we find LIM domain 7 protein (Lmo7) as upregulated upon centrifugation, contributing to mechanoresponse. Third, we discover that mechanical compression force induces a mesenchymal-to-epithelial transition (MET)-like phenotype.

Authors
This work was conducted as an international collaboration between Naoto Ueno's group, which includes Noriyuki Kinoshita, Yutaka Hashimoto, Naoko Yasue, Makoto Suzuki, Ileana M. Cristea and Naoto Ueno.

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Mar 26 2020   Fetal Timeline   Maternal Timeline   News 
Erk2 Graphical Abstract

Eggs of Xenopus Laevis (African clawed frog) are frequently used to study embryonic development because (1) they develop outside of the body and can easily be surgically manipulated or treated with proteins and chemicals that interfere with development (2) embryos become transparent as organogenesis proceeds and are transparent at five days, when organ systems are well defined and subtle morphological defects can be recognized and (3) they have a high tolerance for light exposure.
Information CREDIT National Institutes of Health.
Phospholid by Wikipedia