ADAM interact with large protein complexes to regulate Histone modification, gene expression and splicing.

Cranial neural crest (CNC) cells are key stem cells that contribute to most of the facial structures in all vertebrates. Previous work has shown that multiple ADAM (A Disintegrin And Metalloprotease) cell surface metalloproteases are essential for the induction and migration of the CNC in multiple vertebrate animal models. In Xenopus, we have shown that Adam13 associates with the transcription factor Arid3a to regulate gene expression. Here we show that Adam13 regulates gene expression by modulating Histone modifications globally in the CNC. Furthermore, we show that Arid3a binding to the tfap2a; promoter depends on the presence of Adam13. This association promotes the expression of one tfap2a; variant predominantly expressed in the CNC that uniquely activates the expression of calpain-8, a gene critical for CNC migration. This tfap2a; variant selectively associates with proteins involved with mRNA splicing, a function that is critically affected by the loss of Adam13 in the CNC. Our results suggest that ADAM metalloproteases may act as sensors of the environment that can modulate chromatin availability, leading to changes in gene expression and splicing.