Konikoff CE et al. (2010), Distinct molecular evolutionary mechanisms unde...

ECB-ART-41556

J Mol Evol 2010 Apr 01;704:303-12. doi: 10.1007/s00239-010-9337-z.

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Distinct molecular evolutionary mechanisms underlie the functional diversification of the Wnt and TGFbeta signaling pathways.

Konikoff CE , Wisotzkey RG , Stinchfield MJ , Newfeld SJ .

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The canonical Wnt pathway is one of the oldest and most functionally diverse of animal intercellular signaling pathways. Though much is known about loss-of-function phenotypes for Wnt pathway components in several model organisms, the question of how this pathway achieved its current repertoire of functions has not been addressed. Our phylogenetic analyses of 11 multigene families from five species belonging to distinct phyla, as well as additional analyses employing the 12 Drosophila genomes, suggest frequent gene duplications affecting ligands and receptors as well as co-evolution of new ligand-receptor pairs likely facilitated the expansion of this pathway''s capabilities. Further, several examples of recent gene loss are visible in Drosophila when compared to family members in other phyla. By comparison the TGFbeta signaling pathway is characterized by ancient gene duplications of ligands, receptors, and signal transducers with recent duplication events restricted to the vertebrate lineage. Overall, the data suggest that two distinct molecular evolutionary mechanisms can create a functionally diverse developmental signaling pathway. These are the recent dynamic generation of new genes and ligand-receptor interactions as seen in the Wnt pathway and the conservative adaptation of ancient pre-existing genes to new roles as seen in the TGFbeta pathway. From a practical perspective, the former mechanism limits the investigator''s ability to transfer knowledge of specific pathway functions across species while the latter facilitates knowledge transfer.

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Species referenced: Echinodermata
Genes referenced: anapc1 apc gsk3a LOC100889251 LOC100892350 LOC115918133 LOC115921693 LOC115923729 LOC576611 LOC584189 LOC754949 mxd1 wnt1 wnt6

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	Fig. 1. The canonical Wnt and TGFβ pathways in D. melanogaster. a Wnt pathway. In the absence of a Wnt signal, the destruction complex composed of Axin, APC, and Zw3 phosphorylates Arm (pArm) to tag it for degradation via the ubiquitin–proteasome pathway. In order to activate the pathway, a secreted Wnt ligand binds to unrelated Fz and Arr receptors. Wnt binding leads to the phosphorylation of the Dsh signal transducer. Dsh then inhibits the antagonistic activity of the destruction complex (a double negative mechanism of action), and Arm accumulates in the nucleus. There Arm joins transcription–activation complexes composed of one or more of the transcription factors Pygo, Lgs, and TCF. Arrows indicate positive, and T-bars negative effects on information transfer. b TGFβ pathway: The Dpp ligand binds to Punt a Type II transmembrane receptor serine–threonine kinase, which then recruits the related Tkv Type I receptor and phosphorylates it. Tkv then phosphorylates the R-Smad Mad (pMad). pMad then translocates to the nucleus as a heteromeric complex with the Co-Smad Medea. This multi-Smad complex then regulates the expression of target genes in cooperation with tissue-specific activators and repressors (a linear positive mechanism of action)
	Fig. 2. Maximum likelihood tree of Wnt ligands. Fifty-six Wnt family members from N. vectensis (Nv, green), C. elegans (Ce, purple), D. melanogaster (Dm, blue), S. purpuratus (Sp, red), and M. musculus (Mm, orange) are shown. Twelve small, statistically supported subfamilies are indicated by the name of a M. musculus protein and a bracket (note that Wnt1/6 indicates a statistically supported cluster containing the Wnt1 and Wnt6 subfamilies). The length of the alignment was 1407 amino acids. Statistical confidence was measured via aLRT with values equal to or above 70 considered significant. Branches with aLRT values below 50 are collapsed. The tree is unrooted, and two sequences (Nv Wnt7a and Nv Wnt7b) do not have aLRT values
	Fig. 3. Maximum likelihood trees of Fz and Arrow receptors. Sequences are colored and presented as in Fig. 2. a Twenty-six Fz family members. Six small subfamilies are present. Five subfamilies contain a M. musculus member (brackets), and Ce Fz-2 is alone in the sixth subfamily. The length of the alignment was 1232 amino acids. The tree is unrooted, and two sequences (Mm Fz6 and MmFz3) do not have aLRT values. Note that Ce Fz-1 is also known as Mig-1 and Dm Smoothened does not bind Wg so it was excluded. b Eighteen Arrow family members. Five subfamilies are present. Four subfamilies contain a M. musculus member (brackets), and Dm Yolkless is alone in the fifth subfamily. The alignment was 6113 amino acids. The tree is unrooted and two sequences (Mm LRP5 and Mm LRP6) do not have aLRT values. Note that Mm LRP3 was excluded because the complete sequence was not available
	Fig. 4. Maximum likelihood trees of Dsh and the destruction complex. Sequences are colored and presented as in Fig. 2. a Nine Dsh family members. A single family of all sequences is present. The tree is unrooted and two sequences (Ce Dsh-1 and Ce Dsh-2) do not have aLRT values. The alignment was 978 amino acids. b Four Axin family members. A single family of all sequences is present. The alignment was 1136 amino acids. The tree is unrooted, and two sequences (Mm Axin1 and Mm Axin2) do not have aLRT values. c Six APC family members. A single family of all sequences is present. The alignment was 3852 amino acids. The tree is unrooted, and thus two sequences (Dm APC1 and Dm APC2) do not have aLRT values. Note that APC is missing from the N. vectensis genome. d Seven Zw3 family members. The alignment was 1091 amino acids. The grouping of Ce Gsk-2 with Mm GSKα is not significant. Note that Dm Zw3 is also known as Shaggy. The tree is unrooted, and two sequences (Dm Zw3 and Dm Gskt) do not have aLRT values
	Fig. 5. Maximum likelihood trees of the transcription activation complex. Sequences are colored and presented as in Fig. 2. a Five Pygo family members. Two subfamilies are present, but only the M. musculus subfamily is significant. The alignment was 1159 amino acids. The tree is unrooted, and thus one sequence (Sp Pygo2) does not have an aLRT value. Note that a potential Pygo sequence in N. vectensis, XP_001629729.1 was not included as it is incomplete. b Three Lgs family members. The alignment was 1822 amino acids. No statistics were possible due to small family size. c Nine TCF family members. The alignment was 910 amino acids. A single poorly resolved family of all sequences in present. The tree is unrooted, and two sequences (Mm TCF3 and Mm TCF4) do not have aLRT values. Note that Ce Son-1 is also known as Hmg-1.2 and that Mm TCF1, 3, and 4 are also known as Mm TCF7, 7L, and 7L2, respectively. d Six Arm family members. The alignment was 1024 amino acids. A single poorly resolved family of all sequences is present. The tree is unrooted and two sequences (Ce Wrm-1 and Ce Bar-1) do not have aLRT values. Note that Ce Hmp-2 and Mm Plakoglobin are not involved in Wnt signaling and were excluded from the analysis

References [+] :

Angers, Proximal events in Wnt signal transduction. 2009, Pubmed