Non-junctional role of Cadherin3 in cell migration and contact inhibition of locomotion via domain-dependent, opposing regulation of Rac1

Abstract

Classical cadherins are well-known adhesion molecules responsible for physically connecting neighboring cells and signaling this cell–cell contact. Recent studies have suggested novel signaling roles for “non-junctional” cadherins (NJCads); however, the function of cadherin signaling independent of cell–cell contacts remains unknown. In this study, mesendodermal cells and tissues from gastrula stage Xenopus laevis embryos demonstrate that deletion of extracellular domains of Cadherin3 (Cdh3; formerly C-cadherin in Xenopus) disrupts contact inhibition of locomotion. In both bulk Rac1 activity assays and spatio-temporal FRET image analysis, the extracellular and cytoplasmic Cdh3 domains disrupt NJCad signaling and regulate Rac1 activity in opposing directions. Stabilization of the cytoskeleton counteracted this regulation in single cell migration assays. Our study provides novel insights into adhesion-independent signaling by Cadherin3 and its role in regulating single and collective cell migration.

Global analysis of cell behavior and protein dynamics reveals region-specific roles for Shroom3 and N-cadherin during neural tube closure

“…Our dataset lacked the time resolution to determine precise patterns of N-cadherin movement during apical constriction, but in Z-projections of highly constricted cells, we observed N-cadherin signal not just coincident with, but also basal to, to the apical actin signal ( Figure 4 ). This result is consistent with the emerging understanding of the cell-autonomous roles for cadherins in both actin organization and endocytosis ( Ichikawa et al, 2020 ; Padmanabhan et al, 2017 ; Rebman et al, 2016 ; Sabatini et al, 2011 ; Sako et al, 1998 ; Wu et al, 2015 ).…”

“…Understanding the cellular mechanisms contributing to neural tube closure has long challenged embryologists due to the relatively large number of cells involved and the heterogeneity of their behaviors. Indeed, some of the earliest uses of computer simulation in developmental biology focused on understanding the degree to which neural ectoderm cells constrict their apical surfaces during neural tube closure (Jacobson and Gordon, 1976). Since then, our understanding of neural tube closure has broadly improved.…”

“…This is an important gap in our knowledge, because despite the tacit assumption that cadherins interact with each other and control actomyosin at cell-cell junctions, N-cadherin displays multiple cell-autonomous activities ( Rebman et al, 2016 ; Sabatini et al, 2011 ). Intriguingly, several papers now demonstrate that extra-junctional cadherins at free cell membranes can engage and regulate the actomyosin cortex ( Ichikawa et al, 2020 ; Padmanabhan et al, 2017 ; Sako et al, 1998 ; Wu et al, 2015 ).…”

Global analysis of cell behavior and protein localization dynamics reveals region-specific functions for Shroom3 and N-cadherin during neural tube closure

“…The latter result was surprising because classical cadherins such as N-cadherin are typically known for their function at apical cell-cell junctions. However, a new understanding of the cell-autonomous functions of cadherins, including N-cadherin, is now emerging (Ichikawa et al, 2020; Rebman et al, 2016; Sabatini et al, 2011). Indeed, so-called “extra-junctional cadherins” have been shown to interact with and even regulate the actomyosin cortex in cultured cells and C. elegans embryos (Padmanabhan et al, 2017; Sako et al, 1998; Wu et al, 2015).…”

Novel missense variants in brain morphogenic genes associated with depression and schizophrenia

“…CDH3 , or P-cadherin, although not previously implicated in the pathogenesis of mental disorders, has been shown in several studies to play a critical role in neural cell migration and nerve fiber guidance ( 68 , 69 ). Dysfunction of CDH3 may thus lead to impaired brain formation and function.…”