Extracellular Cleavage of Cadherin-11 by ADAM Metalloproteases Is Essential forXenopusCranial Neural Crest Cell Migration

Abstract

Cell adhesion molecules such as cadherins alternate their expression throughout cranial neural crest (CNC) development, yet our understanding of the role of these molecules during CNC migration remains incomplete. The "mesenchymal" cadherin-11 is expressed in the CNC during migration yet prevents migration when overexpressed in the embryo, suggesting that a defined level of cadherin-11-mediated cell adhesion is required for migration. Here we show that members of the meltrin subfamily of ADAM metalloproteases cleave the extracellular domain of cadherin-11 during CNC migration. We show that a fragment corresponding to the putative shed form of cadherin-11 retains biological activity by promoting CNC migration in vivo, in a non-cell-autonomous manner. Additionally, cleavage of cadherin-11 does not affect binding to ␤-catenin and downstream signaling events. We propose that ADAM cleavage of cadherin-11 promotes migration by modifying its ability to support cell-cell adhesion while maintaining the membrane-bound pool of ␤-catenin associated with the cadherin-11 cytoplasmic domain.

The neural crest

“…This is controlled by Snail/Slug, Foxd3 and Sox9/10 in trunk NC cells (Cheung et al, 2005;McKeown et al, 2013), whereas in the head additional factors such as Ets1, LSox5 and p53 are required (Perez-Alcala et al, 2004;Rinon et al, 2011;Théveneau et al, 2007). In addition, NC cells also express some proteases that are capable of cleaving cadherins such as ADAM10 and ADAM13, further modulating the cell-cell adhesion properties of emigrating NC cells (McCusker et al, 2009;Shoval et al, 2007). These changes, together with a change of integrin activity and local remodelling of the extracellular matrix (ECM), trigger NC migration.…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…In Xenopus, ADAM13 has been shown to initially decrease adhesion of NC cells to the ECM, facilitate delamination from the prospective neural tube and subsequently enable further migration by cleaving ECM substratum ( Fig.1.5.2) (Alfandari et al, 2001;Kee et al, 2007). What's more, ADAM13 has been shown to cleave cadherin-11 generating an extracellular soluble fragment and a membrane-bound cytoplasmic tail, which is crucial for protrusive activities by stimulating small Rho GTPases in cranial NC (Kashef et al, 2009;McCusker et al, 2009). Although the transcriptional control of MMPs/ADAMs proteolytic activity is not fully understood, Zeb2 (Sip1) and Snail2 could be potential regulators of those proteinases (Joseph et al, 2009).…”

Tetraspanin18 is a FoxD3-responsive antagonist of cranial neural crest epithelial to mesenchymal transition that maintains Cadherin6B protein

“…Tetraspanins can associate with membrane proteases such as ADAM metalloproteases (Yáñez-Mó et al, 2011), and Tspan18 could alter ADAM-dependent Cad6B processing. N-cad is processed in trunk neural crest cells by ADAM10 (Shoval et al, 2007), and cadherin-11 cleavage regulates Xenopus cranial neural crest migration (McCusker et al, 2009). However, Cad6B processing has not been defined, precluding evaluation of this scenario.…”

“…Moreover, cadherins typically undergo posttranslational regulation through processing, trafficking, or stabilization (Nishimura and Takeichi, 2009;Thiery et al, 2009). For example, N-cad levels in chick trunk neural crest cells are regulated by processing prior to EMT (Shoval et al, 2007), and cadherin-11 cleavage is required for Xenopus cranial neural crest migration (McCusker et al, 2009). However, posttranslational regulation of cadherins during cranial neural crest EMT has not been determined.…”