Abstract
Nedds are considered a complex and heterogeneous group of proteins, with disparate and diversified roles within cellular homeostasis through distinct types of reactions. Although their well-known importance in multiple diseases and developmental processes, the Nedd evolutionary history is poorly characterized. Thus, here we utilize a comprehensive comparative genomics approach to study the major evolutionary events that shaped Nedd genes in metazoans (Nedd1, Nedd4, Nedd9). Importantly, phylogenetic and syntenic analyses demonstrated that Nedd1 and Nedd4 genes pre-dated the existence of chordates, while Nedd9 emerged in vertebrates. Additionally, our survey suggested that Nedd4 duplicates in vertebrates derive from a whole-genome duplication event. While both phylogeny and synteny did not confirm the evolutionary association among the extant Nedd members, the analysis of the intron/exon junctions unraveled the existence of an ancestral intron code in Nedd genes. Since Nedd genes have a recognized role in vertebrate cardiac development, we shed light on the basic regulatory cascades underlying the Nedd expression in vertebrates’ hearts. By measuring their expression levels in the context of Wnt signaling manipulation in zebrafish, we found that specific genes are differentially expressed in embryonic zebrafish hearts under the control of Wnt signaling. Therefore, our data support a common, yet primitive origin for the extant Nedd genes, unveiling their Wnt-dependent cardiac expression in vertebrates and paving the way to novel analyses in the context of cardiac development of chordates.