Interplay of Eph-Ephrin Signalling and Cadherin Function in Cell Segregation and Boundary Formation

Abstract

The segregation of distinct cell populations to form sharp boundaries is crucial for stabilising tissue organisation, for example during hindbrain segmentation in craniofacial development. Two types of mechanisms have been found to underlie cell segregation: differential adhesion mediated by cadherins, and Eph receptor and ephrin signalling at the heterotypic interface which regulates cell adhesion, cortical tension and repulsion. An interplay occurs between these mechanisms since cadherins have been found to contribute to Eph-ephrin-mediated cell segregation. This may reflect that Eph receptor activation acts through multiple pathways to decrease cadherin-mediated adhesion which can drive cell segregation. However, Eph receptors mainly drive cell segregation through increased heterotypic tension or repulsion. Cadherins contribute to cell segregation by antagonising homotypic tension within each cell population. This suppression of homotypic tension increases the difference with heterotypic tension triggered by Eph receptor activation, and it is this differential tension that drives cell segregation and border sharpening.

Autocrine/Paracrine Slit–Robo Signaling Controls Optic Lobe Development in Drosophila melanogaster

“…Another possibility is the regulation of cell repulsion, in which Slit binds Robo3 in the medulla and other Robo receptors (or a combination of them) in the lobula complex and lamina, which can promote disruption of cell–cell contacts at the interface between neuropils. This mechanism could be similar to the one involved in the separation of ectoderm and mesoderm in the early frog embryo, which depends on two antiparallel Eph-ephrin signaling processes ( Wilkinson, 2021 ) triggered by both tissues ( Rohani et al, 2011 ). Interestingly, one of the downstream effectors found in this study is Rac1, which can rescue the absence of Eph-Ephrin signaling in these tissues.…”

“…At the cellular level, the contribution of differential cell adhesion, cell repulsion, and differential interfacial tension have been well described ( Batlle and Wilkinson, 2012 ; Fagotto, 2014 ). Notably, the signaling pathways upstream of these mechanisms are poorly characterized, and most research in this direction has focused on the Ephrin-Eph pathway ( Cayuso et al, 2015 ; O'Neill et al, 2016 ; Wilkinson, 2021 ).…”

Diversity of Intercellular Communication Modes: A Cancer Biology Perspective

“…Ephs/ephrins and cadherins coordinate their actions to regulate cell segregation and tissue boundary establishment [ 55 , 521 , 522 , 523 ]. In fact, evidence is tilted in favor of an effect of Ephs/ephrins on cadherin-based adhesion, despite the fact that there is evidence to support the reciprocal regulation of Eph/ephrin expression and function by cadherins [ 524 , 525 ].…”

Hindbrain boundaries as niches of neural progenitor and stem cells regulated by the extracellular matrix proteoglycan chondroitin sulphate

“…Remarkably, the HBs have been found to share specific genes and cellular characteristics; they have a fan-shaped morphology, are enriched in extracellular matrix (ECM) and have a reduced cell proliferation rate, as opposed to the neighboring Rhs ( Heyman et al, 1995 ; Lumsden and Keynes, 1989 ). The fact that, unlike Rhs, the repetitive HBs share similar properties, together with their ability to regenerate once removed and their conserved formation in vertebrates, stresses their likely significance ( Guthrie and Lumsden, 1991 ; Pujades, 2020 ; Wilkinson, 2021 ). Similar to other compartment boundaries, the HBs have been suggested to act as local organizing centers for the adjacent Rhs, achieved through secretion of various signaling molecules, such as FGF in chick or Wnt and semaphorins in zebrafish ( Mahmood et al, 1995 ; Pujades, 2020 ; Riley et al, 2004 ; Sela-Donenfeld et al, 2009 ; Terriente et al, 2012 ; Weisinger et al, 2012 ).…”