Cadherin‐6B Proteolysis Controls The Neural Crest Cell Epithelial‐to‐Mesenchymal Transition Through Transcriptional Regulation

Abstract

Listen

Translate article

During epithelial‐to‐mesenchymal transitions (EMTs), cells disassemble cadherin‐based adherens junctions to segregate from the epithelia. Chick premigratory cranial neural crest cells reduce Cadherin‐6B (Cad6B) levels through several mechanisms, including proteolysis, to permit their EMT and migration. Serial processing of Cad6B by ADAMs and γ‐secretase generates an intracellular C‐terminal fragment (CTF2) that could acquire additional functions independent of full‐length Cad6B. Here we report that Cad6B CTF2 possesses a novel pro‐EMT role by up‐regulating EMT effector genes in vivo. Following proteolysis, CTF2 remains associated with β‐catenin, which stabilizes and redistributes both proteins to the cytosol and nucleus, leading to an increase in β‐catenin, CyclinD1, Snail2, and Snail2 promoter‐based GFP expression in vivo. A CTF2 β‐catenin‐binding mutant, however, fails to alter gene expression, indicating that CTF2 modulates β‐catenin‐responsive EMT effector genes. Notably, CTF2 associates with the endogenous Snail2 promoter in the cranial neural crest, providing, for the first time, evidence that a cadherin CTF2 can bind to chromatin in vivo. Furthermore, this association with chromatin is dependent upon an intact β‐catenin‐binding domain within CTF2. Collectively, our data reveal how Cad6B proteolysis orchestrates multiple pro‐EMT regulatory inputs, including a reduction in adhesion within the premigratory neural crest cell population and up‐regulation of the Cad6B repressor Snail2, to ensure proper cranial neural crest cell EMT and appropriate patterning of the vertebrate embryo.Support or Funding InformationThis work was supported by NIH grants R01DE024217 and F32DE022990 and a Research Scholar Grant, RSG‐15‐023‐01‐CSM, from the American Cancer Society.