EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through Local Disruption of Adherens Junctions

Abstract

SummaryThe cochlear sensory epithelium contains a functionally important triangular fluid-filled space between adjacent pillar cells referred to as the tunnel of Corti. However, the molecular mechanisms leading to local cell-cell separation during development remain elusive. Here we show that EphA4 associates with ADAM10 to promote the destruction of E-cadherin-based adhesions between adjacent pillar cells. These cells fail to separate from each other, and E-cadherin abnormally persists at the pillar cell junction in EphA4 forward-signaling-deficient mice, as well as in the presence of ADAM10 inhibitor. Using immunolabeling and an in situ proximity ligation assay, we found that EphA4 forms a complex with E-cadherin and its sheddase ADAM10, which could be activated by ephrin-B2 across the pillar cell junction to trigger the cleavage of E-cadherin. Altogether, our findings provide a new molecular insight into the regulation of adherens junctions, which might be extended to a variety of physiological or pathological processes.

Proteolytic Cleavage of Receptor Tyrosine Kinases

“…Additionally, a previous study also suggested that EphA4 can associate with ADAM10 to form a complex with ADAM10 and E-cadherin in the plasma membranes of pillar cells [ 86 ]. This study suggests that EphA4 promotes the destruction of E-cadherin-based adhesions between adjacent pillar cells [ 86 ]; and that, with the presence of Ephrin-B2, EphA4 can promote the activation of ADAM10, which results in the cleavage of E-cadherin [ 86 ]. In addition, EphA4 is a member of dependence receptor [ 87 ].…”

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

“…Furthermore, blocking of ADAM10 disrupts Eph receptor-mediated cell segregation in cell culture assays and in the intestinal epithelium ( Solanas et al, 2011 ). A related role has been found in the cochlear sensory epithelium, in which EphA4-ephrinB2 interactions lead to E-cadherin cleavage by ADAM10 that enables separation of adjacent cells ( Defourny et al, 2019 ). In addition to cleaving E-cadherin, ADAM10 mediates cleavage of ephrinA ligands from the cell surface following interaction with EphA receptors ( Hattori et al, 2000 ; Janes et al, 2005 ; Atapattu et al, 2012 ).…”

ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease

“…ADAM10 participates in cell-cell contact in other systems, such as the cochlear sensory epithelium. EphA4 in fact forms a complex with E-cadherin and its sheddase ADAM10, which promotes the destruction of E-cadherin-based adhesions [ 91 ].…”