ADAM13 is Required for Xenopus Head Development by Regulating Class B Ephrin and Wnt Signaling

Abstract

Protein ectodomain shedding by disintegrin metalloproteinases (ADAMs) has emerged as a key regulatory event in cell signaling. We previously showed that an ADAM metalloproteinase, ADAM13, is expressed in cranial neural crest (CNC) cells in Xenopus laevis, and that overexpression of a protease dead mutant of ADAM13 prevents CNC migration. To further understand the roles of this gene in vertebrate development, we carried out loss‐of‐function studies in X. tropicalis, a closely related frog species with a diploid genome. Knockdown of ADAM13 by antisense morpholinos (MOs) resulted in abnormal head development, including reduced CNC induction and perturbed eye field patterning. The metalloproteinase activity of ADAM13 was required for these functions in vivo. Using cultured cells, we identified membrane‐bound ephrins (Efns) B1 and B2 as substrates for ADAM13. Knockdown of ADAM13 protected endogenous EfnB1/B2 in developing embryos, indicating that these two ephrins are in vivo substrates for ADAM13. The defects caused by ADAM13 MO could be rescued by blocking forward EfnB signaling, restoring canonical Wnt signaling, or by ectopic expression of the transcription factor Slug. Our data suggest a novel EfnB‐Wnt‐Slug signaling cascade through which ADAM13 controls CNC induction and eye field patterning.