Torres-Aguila NP et al. (2022), Evolutionary diversification of the canonical W...

XB-ART-60762

Dev Growth Differ 2022 Apr 01;643:120-137. doi: 10.1111/dgd.12771.

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Evolutionary diversification of the canonical Wnt signaling effector TCF/LEF in chordates.

Torres-Aguila NP , Salonna M , Hoppler S , Ferrier DEK .

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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.

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Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: ctbp2 lef1 tcf7 tcf7l1 tcf7l2
GO keywords: canonical Wnt signaling pathway

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	FIGURE 1. Synteny analysis. (a) Representation of Genomicus synteny results of TCF7L1 paralogs in teleosts. Blue, TCF7L1 gene. Dark/light gray, genes with paralogy relationships comparable to TCF7L1a/b paralogy; the dark-gray genes are those in the D. rerio TCF7L1a paralogon, and light gray in the D. rerio TCF7L1b paralogon. Dark green, genes whose locations are conserved within TCF7L1a paralogons. Light green, genes whose locations are conserved within TCF7L1b paralogons. (b) Dot plots of genomic sequence comparison between P. marinus and E. tridentatus and L. reissneri. Left panels show genome versus genome comparison; right panels show TCF-containing chromosome comparisons. Axes indicate chromosome number
	FIGURE 2. Phylogenetic tree of TCF/LEF family genes. Orange, yellow, dark-blue, and light-blue boxes highlight TCF7, LEF1, TCF7L1, and TCF7L2 ohnolog subfamilies respectively. Red square highlights the cyclostome gene clade. Node values are maximum-likelihood percentage bootstrap support. The circles in the node indicate a support value of 100
	FIGURE 3. TCF gene models. Composite gene models of the species included in this study (specified in Appendix S1). Boxes represent exons, and lines represent splicing. Arrows represent transcription start sites. Widely conserved exons are numbered with Roman numerals; lower-case letters indicate species-specific exons (a, conserved within mammals; b, conserved within birds and reptiles; c, conserved within teleosts; d, conserved within teleosts except Danio rerio; e, conserved within reptiles). “M” represents the conserved methionine found on exon III. Red asterisks represent early stop codons. Question mark indicates lack of unambiguous experimental evidence. Following previous consensus, C-terminal isoforms are named with capital letters (B, C, D, E, F, N). The color codes of the exons are as follows: green, β-catenin binding domain; pink, LVPQ motif; orange, SxxSS motif; yellow, co-repressor helper domain; red = co-repressor domain; dark blue, High Mobility Group box; turquoise, nuclear localization signal; light blue, C-clamp domain; purple, CtBP motif; gray, exon with no wider sequence conservation. Green squares highlight vertebrate innovations, and orange square highlights a chordate innovation. WGD, whole-genome duplications
	FIGURE 4. Amino-acid sequence alignment of parts of TCF/LEF proteins. Intensity of gray coloration represents degree of conservation: the higher the intensity, the greater the conservation. (a) TCF/LEF exon III alignment. Orange and yellow squares highlight TCF7 and LEF1 alternative translation start sites, respectively. (b) TCF/LEF HMG-box alignment. Orange, yellow, and blue squares highlight specific amino-acid changes for TCF7, LEF1, and TCF7L1, respectively
	FIGURE 5. Distribution of CLGQ cyclostome orthologs in gnathostome TCF/LEF neighborhoods and P. marinus TCF-containing chromosomes. LEF1nbh, LEF1 neighborhood; TCF7nbh, TCF7 neighborhood; TCF7L1nbh, TCF7L1 neighborhood; TCF7L2nbh, TCF7L2 neighborhood; Shared_nbh, shared neighborhood (ortholog present in more than one gnathostome TCF/LEF neighborhood); Other_nbh, other neighborhood (ortholog not present in any gnathostome TCF/LEF neighborhood); n = number of genes
	Supplemental Figure 1. Alignment and phylogeny of cyclostome TCFs. A) Alignment of Cyclostome TCF amino-acid sequences, including the partial sequences of L. planeri TCFc and TCFd, and P. marinus TCFc.
	Supplemental Figure 1. B) Maximum-likelihood tree using the sequence alignment from A. Node values are the percentage bootstrap support values. The circles in the node indicates a support value of 100. The tree is rooted with non-chordate sequences as the outgroup.
	Supplemental Figure 2. Gnathostome TCF/LEF phylogeny. Maximum-likelihood tree using the sequence alignment from Supplemental File 2 excluding the cyclostome sequences. Node values are the percentage bootstrap support values. The circles in the node indicate a support value of 100. Tree is rooted with non-chordate sequences as the outgroup.
	Supplemental Figure 3. Distribution of CLGQ genes across P. marinus chromosomes. N_exp: number of CLGQ genes expected. N_obs: Number of CLGQ genes observed.

References [+] :

Arce, Diversity of LEF/TCF action in development and disease. 2006, Pubmed