Evolution of the Wnt pathways

Abstract

Wnt proteins mediate the transduction of at least three major signaling pathways that play central roles in many early and late developmental decisions. They control diverse cellular behaviors, such as cell fate decisions, proliferation, and migration, and are involved in many important embryological events, including axis specification, gastrulation, and limb, heart, or neural development. The three major Wnt pathways are activated by ligands, the Wnts, which clearly belong to the same gene family. However, their signal is then mediated by three separate sets of extracellular, cytoplasmic, and nuclear components that are pathway-specific and that distinguish each of them. Homologs of the Wnt genes and of the Wnt pathways components have been discovered in many eukaryotic model systems and functional investigations have been carried out for most of them. This review extracts available data on the Wnt pathways, from the protist Dictyostelium discoideum to humans, and provides from an evolutionary prospective the overall molecular and functional conservation of the three Wnt pathways and their activators throughout the eukaryotic superkingdom.

Fig. 1.1

Schematic eukaryotic phylogenetic representation. All organisms discussed in this volume of Methods in Molecular Biology are represented in this tree. Amoebozoa are protists; however, their relative position on the eukaryotic tree relative to plant and fungi remains controversial.

Fig. 1.2

Distribution of Wnt proteins throughout the eukaryotic superkingdom. A square represents each gene found in the corresponding genome by protein subfamily. A 0 designates the absence of homologs of that subfamily in the corresponding genome. A question mark indicates orthology uncertainties. Genomes used are: amoebozoa, Dictyostelium discoideum; cnidarians, Nematostella vectensis; protostomes, Drosophila melanogaster and Caenorhabditis elegans (unless stipulated as coming from the mosquito Anopheles gambiae); echinoderms, Strongylocentrotus purpuratus; vertebrates, Homo sapiens (Adapted and Updated from ref. 12).

Fig. 1.3

Comparison of canonical Wnt signal transduction models among eukaryotes. (A) In most bilaterians, the canonical Wnt pathway is activated by a Wnt/Frizzled interaction, which results in the activation of the cytoplasmic effector Dsh that in turn inhibits the antagonistic GSK3, releasing β-catenin, which now activates TCF/Lef. (B) In the protist Dictyostelium discoideum, GSK3 and β-catenin homologs, GskA and Aar respectively, are activated by the binding of cAMP to its receptor cAR3. This interaction leads to the activation of GskA, which then phosphorylates and activates Aar. (C) In C. elegans, two Wnt pathways involving GSK3 and two distinct β-catenin homologs are observed. While the Wnt/BAR-1 pathway evolved as the classic bilaterians canonical Wnt pathway (right), the Wnt/WRM-1 pathway (left) is similar to the GskA/Aar pathway described in Dictyostelium. Wnt (MOM-2)/Frizzled (MOM-5) interaction induces the activation of the GSK3 homolog SGG-1, which activates WRM-1 by phosphorylation that in turn inhibits the TCF/Lef homolog POP-1 activity. Arrows within this figure do not necessarily represent direct interaction between the molecules.

Fig. 1.4

Schematic representation of the two most studied non-canonical pathways. (A) The Planar Cell Polarity pathway. Upon interaction of a Wnt ligand with a Frizzled receptor and activation of the cytoplasmic protein Disheveled, the signal is transduced through two distinct small G proteins Rho and Rac, which convey cell polarity via their respective effectors ROCK and JNK. To establish polarity, however, the membrane receptor Strabismus is also activated but in the neighboring cell (in gray), where via Prickle it inhibits the PCP pathway by sequestering Disheveled. (B) The Wnt/Ca²⁺ pathway. Activation of the Wnt/calcium pathway leads to the activation of the key component PLC and an increase in intracellular calcium levels, which induces activation of the calcium-sensitive proteins Calcineurin, CamKII, and PKC.