FAK is required for tension-dependent organization of collective cell movements in Xenopus mesendoderm

Abstract

Collective cell movements are integral to biological processes such as embryonic development and wound healing and also have a prominent role in some metastatic cancers. In migrating Xenopus mesendoderm, traction forces are generated by cells through integrin-based adhesions and tension transmitted across cadherin adhesions. This is accompanied by assembly of a mechanoresponsive cadherin adhesion complex containing keratin intermediate filaments and the catenin-family member plakoglobin. We demonstrate that focal adhesion kinase (FAK), a major component of integrin adhesion complexes, is required for normal morphogenesis at gastrulation, closure of the anterior neural tube, axial elongation and somitogenesis. Depletion of zygotically expressed FAK results in disruption of mesendoderm tissue polarity similar to that observed when expression of keratin or plakoglobin is inhibited. Both individual and collective migrations of mesendoderm cells from FAK depleted embryos are slowed, cell protrusions are disordered, and cell spreading and traction forces are decreased. Additionally, keratin filaments fail to organize at the rear of cells in the tissue and association of plakoglobin with cadherin is diminished. These findings suggest that FAK is required for the tension-dependent assembly of the cadherin adhesion complex that guides collective mesendoderm migration, perhaps by modulating the dynamic balance of substrate traction forces and cell cohesion needed to establish cell polarity.

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

“…Furthermore, signals that emanate from focal adhesions guide the formation of cadherin-based adhesions during gastrulation in Xenopus (Bjerke et al, 2014). There, deletion of FAK with morpholinos disrupts the actin cytoskeleton, alters the spatial distribution of keratin and reduces the binding of plakoglobin (also known as JUP and γ-catenin) to C-cadherin in mesendoderm explants.…”

“…There, deletion of FAK with morpholinos disrupts the actin cytoskeleton, alters the spatial distribution of keratin and reduces the binding of plakoglobin (also known as JUP and γ-catenin) to C-cadherin in mesendoderm explants. These changes are associated with impaired cell spreading and traction force generation and ultimately delay collective cell migration as well as disrupting mesendoderm tissue polarity (Bjerke et al, 2014).…”

Molecular model for force production and transmission during vertebrate gastrulation

“…Although protrusive activity does not itself generate traction forces, in its role of 'getting a new grip', it is universally associated with a subsequent traction force in traction-force microscopy of both single cells and groups of cells (Beningo et al, 2001(Beningo et al, , 2006Harris et al, 1980;Hind et al, 2015;Lo et al, 2004Lo et al, , 2000. Although integrinmediated traction forces have received most experimental attention, C-cadherin adhesion also functions in force transduction in Xenopus (Bjerke et al, 2014;Schwartz and DeSimone, 2008) and E-cadherin-mediated cell traction forces have also been seen during Drosophila border cell migration (Cai et al, 2014;Fulga and Rørth, 2002;Geisbrecht and Montell, 2002;Rauzi et al, 2010).…”

“…An alternative idea is that cell intercalation occurs by cell-on-cell traction (Keller et al, 2000(Keller et al, , 1992 and this traction could be mediated by calciumdependent cadherin adhesion (Lee and Gumbiner, 1995). C-cadherin is the predominate cadherin in Xenopus tissues undergoing CE and its activity has been shown to be modulated during both CE and mesendoderm migration (Bjerke et al, 2014;Brieher and Gumbiner, 1994;Schwartz and DeSimone, 2008;Zhong et al, 1999).…”

A Molecular Model for Cell Intercalation during Convergence and Extension: Interacting Cytoskeletal Elements and Myosin Regulation.

“…An alternate idea is that cell intercalation occurs by cell-on-cell traction , and this traction could be mediated by calcium-dependent cadherin adhesion (Lee and Gumbiner, 1995). C-Cadherin is the predominate cadherin in Xenopus tissues undergoing CE, and its activity has been shown to be modulated during both CE and mesendoderm migration (Bjerke et al, 2014;Brieher and Gumbiner, 1994;Schwartz and DeSimone, 2008;Zhong et al, 1999). …”