Abstract
Wnt signaling is essential during animal development and regeneration, but also plays an important role in diseases such as cancer and diabetes. The canonical Wnt signaling pathway is one of the most conserved signaling cascades in the animal kingdom, with the T‐cell factor/lymphoid enhancer factor (TCF/LEF) proteins being the major mediators of Wnt/β‐catenin‐regulated gene expression. In comparison with invertebrates, vertebrates possess a high diversity of TCF/LEF family genes, implicating this as a possible key change to Wnt signaling at the evolutionary origin of vertebrates. However, the precise nature of this diversification is only poorly understood. The aim of this study is to clarify orthology, paralogy, and isoform relationships within the TCF/LEF gene family within chordates via in silico comparative study of TCF/LEF gene structure, molecular phylogeny, and gene synteny. Our results support the notion that the four TCF/LEF paralog subfamilies in jawed vertebrates (gnathostomes) evolved via the two rounds of whole‐genome duplications that occurred during early vertebrate evolution. Importantly, gene structure comparisons and synteny analysis of jawless vertebrate (cyclostome) TCFs suggest that a TCF7L2‐like form of gene structure is a close proxy for the ancestral vertebrate structure. In conclusion, we propose a detailed evolutionary path based on a new pre‐whole‐genome duplication vertebrate TCF gene model. This ancestor gene model highlights the chordate and vertebrate innovations of TCF/LEF gene structure, providing the foundation for understanding the role of Wnt/β‐catenin signaling in vertebrate evolution.
Highlights
Wnt signaling is a cell-to-cell signaling mechanism highly conserved in the animal kingdom (Hoppler & Moon, 2014)
It was previously assumed that four paralogs (TCF7, LEF1, TCF7L1, and TCF7L2) evolved in vertebrates from a single invertebrate TCF gene through two rounds of whole-genome duplications (2R WGD), with TCF7 ohnologs appearing to represent the most prototypical and TCF7L2 ohnologs presumed to be the most derived via evolving most vertebrate-specific innovations subsequent to these WGD-associated T-cell factor/lymphoid enhancer factor (TCF/LEF) gene duplications (Hoppler & Waterman, 2014)
Our comprehensive analysis of deuterostome sequence information strongly supports an evolutionary emergence via 2R WGD of a widely conserved four-ohnolog standard from a single pre- vertebrate TCF gene
Summary
Wnt signaling is a cell-to-cell signaling mechanism highly conserved in the animal kingdom (Hoppler & Moon, 2014). Without Wnt signaling (with low levels of nuclear β- catenin) they act as transcriptional repressors, but when Wnt signaling is present (with high levels of nuclear β-catenin) they act as transcriptional activators This bimodal activity is functionally mediated through different protein domains and motifs in the coding sequence of TCF/LEF genes (Cadigan & Waterman, 2012; Hoppler & Waterman, 2014). Despite vertebrate and invertebrate TCF/LEF genes sharing some inherited ancestral structures and functions, it is still unknown to what extent these characteristics are either shared or have been apportioned among vertebrate paralogs, leading to redundancy, sub-functionalization, and/or neofunctionalization within this gene family This diversity in vertebrate TCF/LEF genes is likely key to understanding the evolution of vertebrate Wnt signaling, and possibly many aspects of vertebrate evolution itself. This diversity of species outside the gnathostome clade sheds light on TCF evolution at the very base of the vertebrates, from the last common ancestor of chordates via the pre-WGD last common ancestor of vertebrates to the four subfamilies we find in vertebrates
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