EphA4 Activity Causes Cell Shape Change and a Loss of Cell Polarity in Xenopus laevis embryos

Winning, Robert S.; Wyman, Tammy L.; Walker, Glenn K.

doi:10.1046/j.1432-0436.2001.680206.x

Cited by 19 publications

(16 citation statements)

References 28 publications

(38 reference statements)

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“…Similarly, EphA4 activation in early Xenopus embryos disrupted cadherin-dependent cell adhesion. Cells acquire a rounded morphology, lose apical microvilli, and the apical/basolateral boundary is also lost, indicating that cells lost their apical/basolateral polarity (53). The molecular bases of these changes are unknown.…”

Section: Cd25mentioning

confidence: 99%

Thymic Alterations in EphA4-Deficient Mice

Múñoz

Alfaro

García‐Ceca

et al. 2006

The Journal of Immunology

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In the present work, we have demonstrated in vivo an altered maturation of the thymic epithelium that results in defective T cell development which increases with age, in the thymus of Eph A4-deficient mice. The deficient thymi are hypocellular and show decreased proportions of double-positive (CD4+CD8+) cells which reach minimal numbers in 4-wk-old thymi. The EphA4 −/− phenotype correlates with an early block of T cell precursor differentiation that results in accumulation of CD44−CD25+ triple-negative cells and, sometimes, of CD44+CD25− triple-negative thymocytes as well as with increased numbers of apoptotic cells and an important reduction in the numbers of cycling thymocytes. Various approaches support a key role of the thymic epithelial cells in the observed phenotype. Thymic cytoarchitecture undergoes profound changes earlier than those found in the thymocyte maturation. Thymic cortex is extremely reduced and consists of densely packed thymic epithelial cells. Presumably the lack of forward Eph A4 signaling in the Eph A4 −/− epithelial cells affects their development and finally results in altered T cell development.

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Section: Cd25mentioning

confidence: 99%

Thymic Alterations in EphA4-Deficient Mice

Múñoz

Alfaro

García‐Ceca

et al. 2006

The Journal of Immunology

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“…EphA4 is expressed in the mesoderm (Winning and Sargent, 1994) to contribute to boundary maintenance (Park et al, 2011). Its ectopic expression in ectoderm diminishes cell adhesion (Winning et al, 1996(Winning et al, , 2001) through Nck-mediated recruitment of Pak1, which in turn prevents activation of RhoA (Winning et al, 2002;Bisson et al, 2007). Activation of Paks by recruitment to receptor tyrosine kinases is common (Lu et al, 1997), and Paks are prominently involved in regulating the cytoskeleton, but also in transcriptional control (Bokoch, 2003;Hofmann et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

EphA4-dependent Brachyury expression is required for dorsal mesoderm involution in the Xenopus gastrula

et al. 2014

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Xenopus provides a well-studied model of vertebrate gastrulation, but a central feature, the movement of the mesoderm to the interior of the embryo, has received little attention. Here, we analyze mesoderm involution at the Xenopus dorsal blastopore lip. We show that a phase of rapid involution -peak involution -is intimately linked to an early stage of convergent extension, which involves differential cell migration in the prechordal mesoderm and a new movement of the chordamesoderm, radial convergence. The latter process depends on Xenopus Brachyury, the expression of which at the time of peak involution is controlled by signaling through the ephrin receptor, EphA4, its ligand ephrinB2 and its downstream effector p21-activated kinase. Our findings support a conserved role for Brachyury in blastopore morphogenesis.

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“…However, Xenopus embryos express several Eph receptors and ephrin ligands, and these receptors and ligands have been shown to be important for development (Winning and Sargent, 1994;Jones et al, 1995;Scales et al, 1995;Tanaka et al, 2003;Lee et al, 2006). Activation of EphA4 in early Xenopus embryos induces a loss of blastomere adhesion (loss-of-adhesion), which provides a unique, simple and reliable physiological readout of receptor activity (see Figure 1A; Winning et al, 1996Winning et al, , 2001Winning et al, , 2002. The normal epithelial structure of the blastocoel roof is disrupted in these embryos, leading to an occlusion of the blastocoel.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the EphA4 phenotype is probably due in greater part to a down-regulation of normal cell-cell adhesion via adherens junctions. More recently, this mutant phenotype was shown to be associated with a loss of microvilli and of apical/basolateral polarity (Winning et al, 2001) and to be rescued by activated RhoA (Winning et al, 2002). This suggested that EphA4 activation suppressed Rho activity, but no signaling pathway was identified.…”

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confidence: 99%

EphA4 Signaling Regulates Blastomere Adhesion in the Xenopus Embryo by Recruiting Pak1 to Suppress Cdc42 Function

Bisson

Poitras

Mikryukov

et al. 2007

MBoC

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The control of cell adhesion is an important mechanism by which Eph receptors regulate cell sorting during development. Activation of EphA4 in Xenopus blastulae induces a reversible, cell autonomous loss-of-adhesion and disruption of the blastocoel roof. We show this phenotype is rescued by Nck␤ (Grb4) dependent on its interaction with EphA4. Xenopus p21 Cdc42/Rac -activated kinase xPAK1 interacts with Nck, is activated in embryo by EphA4 in an Nck-dependent manner, and is required for EphA4-induced loss-of-adhesion. Ectopic expression of xPAK1 phenocopies EphA4 activation. This does not require the catalytic activity of xPAK1, but it does require its GTPase binding domain and is enhanced by membrane targeting. Indeed, membrane targeting of the GTPase binding domain (GBD) of xPAK1 alone is sufficient to phenocopy EphA4 loss-of-adhesion. Both EphA4 and the xPAK1-GBD down-regulate RhoA-GTP levels, and consistent with this, loss-of-adhesion can be rescued by activated Cdc42, Rac, and RhoA and can be epistatically induced by dominant-negative RhoA. Despite this, neither Cdc42 nor Rac activities are down-regulated by EphA4 activation or by the xPAK1-GBD. Together, the data suggest that EphA4 activation sequesters active Cdc42 and in this way down-regulates cell-cell adhesion. This novel signaling pathway suggests a mechanism for EphA4-guided migration. INTRODUCTIONDevelopment of the vertebrate body plan involves several stages during which embryonic cells must migrate to form new structures. The regulation of these migration events is complex, being controlled at the levels of cell-cell adhesion, cytoskeletal dynamics, intercellular signaling, and genetic reprogramming. However, the fundamental problem posed by cell migration is very simple: how does a cell find its way to its target site and recognize that site once there? In greater part, the answer seems to be by regulating cell adhesion (Steinberg, 1996;Tepass et al., 2002). The large family of Eph tyrosine kinase (TK) receptors and their membrane-bound ephrin ligands have been recognized as key regulators of cell migration, adhesion, and targeting in a broad range of tissues (for reviews, see Cowan and Henkemeyer, 2002;Kullander and Klein, 2002;Tepass et al., 2002;Murai and Pasquale, 2003;Pasquale, 2005). These receptor-ligand combinations seem to control cell migration and cell targeting predominantly by regulating cell adhesion. The paradigm for these receptors is the contact-mediated repulsion of Ephexpressing axon growth cones by ephrin-expressing cells.During this rapid repulsion event, the growth cone cytoskeleton is seen to collapse, linking Eph signaling directly with cytoskeletal dynamics. But Eph and ephrin signaling has also been widely implicated in the establishment or maintenance of tissue boundaries, especially during development, e.g., hindbrain segment boundaries, and in targeted cell migration, e.g., cranial neural crest migration. Ectopic expression of EphA4 or B2 and ephrin B2 in separate populations of zebrafish blastomeres abolishes cell mi...

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EphA4 Activity Causes Cell Shape Change and a Loss of Cell Polarity in Xenopus laevis embryos

Cited by 19 publications

References 28 publications

Thymic Alterations in EphA4-Deficient Mice

Thymic Alterations in EphA4-Deficient Mice

EphA4-dependent Brachyury expression is required for dorsal mesoderm involution in the Xenopus gastrula

EphA4 Signaling Regulates Blastomere Adhesion in the Xenopus Embryo by Recruiting Pak1 to Suppress Cdc42 Function

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