Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13

Abstract

During vertebrate gastrulation, canonical Wnt signaling induces the formation of neural plate border (NPB). Wnt is also thought to be required for the subsequent specification of neural crest (NC) lineage at the NPB, but the direct evidence is lacking. We found previously that the disintegrin metalloproteinase ADAM13 is required for Wnt activation and NC induction in Here, we report that knockdown of ADAM13 or its close paralog ADAM19 severely downregulates Wnt activity at the NPB, inhibiting NC specification without affecting earlier NPB formation. Surprisingly, ADAM19 functions nonproteolytically in NC specification by interacting with ADAM13 and inhibiting its proteasomal degradation. Ectopic expression of stabilized ADAM13 mutants that function independently of ADAM19 can induce the NC marker/specifier in the future epidermis via Wnt signaling. These results unveil the essential roles of a novel protease-protease interaction in regulating a distinct wave of Wnt signaling, which directly specifies the NC lineage.

The RNA helicase DDX3 induces neural crest by promoting AKT activity

“…To investigate directly the roles of DDX3 in Wnt signaling during NC induction, we took advantage of a transgenic Wnt reporter line (Tran et al, 2010). Using this reporter line, we showed recently that there is strong endogenous Wnt signaling at the NPB during NC induction (Li et al, 2018). As expected, this Wnt activity was inhibited by KD of DDX3 ( Fig.…”

“…These NPB specifiers subsequently induce other transcription factors, including Snai2, FoxD3 and Sox9 (the "NC specifiers"), to specify the NC fate within the NPB (Bronner and Simões-Costa, 2016;Simões-Costa and Bronner, 2015;Stuhlmiller and Garcia-Castro, 2012). A major signaling pathway that induces the NC in non-mammalian vertebrates is canonical Wnt/b-catenin signaling (hereinafter referred to as "Wnt signaling"), which is required for both the initial formation of the NPB and the subsequent specification of the NC (Li et al, 2018;Prasad et al, 2019). Similarly, the induction of NC from human embryonic stem (ES) cells or induced pluripotent stem (iPS) cells also requires the activation of Wnt signaling (Gomez et al, 2019;Leung et al, 2016;Menendez et al, 2011;Mica et al, 2013), indicating that Wnt function in NC induction is conserved during vertebrate evolution.…”

Specification and formation of the neural crest: Perspectives on lineage segregation

“…A recent study further elaborated on the role of ADAM13 during neural crest induction. This study proposed a non‐proteolytic role for ADAM19 in stabilizing ADAM13 to promote Wnt signaling during neural crest induction in Xenopus embryos (Li et al, ). ADAM19 loss‐of‐function and gain‐of‐function analyses in Xenopus embryos validated its requirement during neural crest induction in a Wnt‐dependent manner (Li et al, ).…”

Neural crest delamination and migration: Looking forward to the next 150 years

“…Inhibition of either ADAM9, 13 or 19 by Morpholino leads to an increase of the amount of full length Cadherin‐11 (McCusker, Cousin, Neuner, & Alfandari, ). However, the effect ADAM19 knockdown is not due to a role in processing cadherin‐11 but its ability to bind to ADAM13 to prevent its ubiquitination (Li et al, ). This cleavage generates a truncated form of Cadherin‐11, which has lost its binding capacity, and an N‐terminal fragment, EC1–3 (McCusker et al, ).…”