WNTs modulate cell fate and behavior during vertebrate development

Mammalian Genome, 1999

Evolution & Development, 2012

Genes encoding Wnt ligands are crucial in body patterning and are highly conserved among metazoans. Given their conservation at the protein-coding level, it is likely that changes in where and when these genes are active are important in generating evolutionary variations. However, we lack detailed knowledge about how their deployment has diverged. Here, we focus on four Wnt subfamilies (Wnt2, Wnt5, Wnt7, and Wnt8) in mammalian and avian species, consisting of a paralogous gene pair in each, believed to have duplicated in the last common ancestor of vertebrates. We use threedimensional imaging to capture expression patterns in detail and carry out systematic comparisons. We find evidence of greater divergence between these subgroup paralogues than the respective orthologues, consistent with some level of subfunctionalization/neofunctionalization in the common vertebrate ancestor that has been conserved. However, there were exceptions; in the case of chick Wnt2b, individual sites were shared with both mouse Wnt2 and Wnt2b. We also find greater divergence, between paralogues and orthologues, in some subfamilies (Wnt2 and Wnt8) compared to others (Wnt5 and Wnt7) with the more highly similar expression patterns showing more extensive expression in more structures in the embryo. Wnt8 genes were most restricted and most divergent. Major sites of expression for all subfamilies include CNS, limbs, and facial region, and in general there were more similarities in gene deployment in these territories with divergent patterns featuring more in organs such as heart and gut. A detailed comparison of gene expression patterns in the limb showed similarities in overall combined domains across species with notable differences that may relate to lineagespecific morphogenesis.

Current Biology, 2002

availability of the full sequence of the fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and human genomes allows us to study the full set of Benjamin Prud'homme, Nicolas Lartillot, Guillaume Balavoine, André Adoutte, and Michel Vervoort 1 Evolution et Dé veloppement des Protostomiens Wnt genes that are present in these organisms. Centre de Gé né tique Molé culaire -UPR 2167 CNRS 1, Av. de la Terrasse Derivation of a Comprehensive Set of Wnt Genes 91198 Gif-sur-Yvette Cedex in Bilateria France Amplification by PCR with degenerate primers yielded 320-pb fragments of six different Wnt genes from the annelid Platynereis dumerilii and four from the gastro-Summary pod Patella vulgata. Vector-anchored RACE-PCR was used to isolate the full length (or at least larger frag-The Wnt gene family encodes secreted signaling molements) of the corresponding genes (see the Experimencules that control cell fate specification, proliferation, tal Procedures). We have aligned the Wnt domains of polarity, and movements during animal development these newly obtained Wnt sequences to those of a large [1-3]. We investigate here the evolutionary history of set of Wnt genes retrieved from databases. this large multigenic family. Wnt genes have been al-

Cell, 2005

known, the mechanism of activation remains controver-1 Division of Developmental Biology sial. In Xenopus, sperm entry activates oriented micro-Cincinnati Children's Research Foundation tubule polymerization that causes dorsally directed cy-3333 Burnet Avenue toplasmic and organelle movements within a thin layer Cincinnati, Ohio 45229 of cortical cytoplasm during the first cell cycle (Elinson 2 Department of Life Sciences and Rowning, 1988; Houliston and Elinson, 1991; Lara-The University of Tokyo bell et al., 1996; Vincent et al., 1986). One hypothesis 3-8-1 Komaba, Meguro-ku suggests that this movement concentrates β-catenin Tokyo 153-8902 (Rowning et al., 1997) or dishevelled protein (Miller et Japan al., 1999) on the dorsal side during the cleavage stages and that this activates the Wnt pathway intracellularly. Another model suggests that the downregulation on the Summary dorsal side of the inhibitor, GSK-3β, establishes an asymmetry of β-catenin function (Dominguez and Wnt signaling pathways play essential roles in pat-Green, 2000

Frontiers in Bioscience, 2011

2000

The Wnt family of secreted signaling molecules is conserved throughout the animal kingdom. Wnt signaling plays critical roles during embryonic development and mutations leading to the overactivation of the Wnt pathway have been linked to cancer. Wnt signals are transduced intracellularly by the Frizzled family of receptors. Moreover, proteoglycans and the co-receptors LRP5 and -6 participate in the transmission of

Methods in Molecular Biology, 2008

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.

Current Opinion in Genetics & Development, 1999

Members of the Wnt family of secreted glycoproteins participate in many signalling events during development. Recent findings suggest that Wnt signals can sometimes play a permissive role during cell-fate assignment. Wnt proteins have been shown to interact with a number of extracellular and cell-surface proteins, whereas many intracellular components of the Wnt-signalling pathway are also involved in other cellular functions. The consequences of Wnt signalling can be affected by members of the MAP kinase family. These observations suggest that the future understanding of Wnt signalling may require models that are based on a signalling network rather than a single linear pathway.

AJP: Renal Physiology, 2007

The canonical WNT signaling pathway plays a crucial role in patterning of the embryo during development, but little is known about the specific developmental events, which are under WNT control. To understand more about how the WNT pathway orchestrates mammalian organogenesis, we studied the canonical -catenin mediated WNT signaling pathway in kidneys of mice bearing a -catenin responsive TCF/ Gal reporter transgene. In metanephric kidney, intense canonical WNT signaling was evident in epithelia of the branching ureteric bud and in nephrogenic mesenchyme during its transition into renal tubules. WNT signaling activity is rapidly downregulated in maturing nephrons and becomes undetectable in post-natal kidney.

The Wnt family of secreted signaling molecules is conserved throughout the animal kingdom. Wnt signaling plays critical roles during embryonic development and mutations leading to the overactivation of the Wnt pathway have been linked to cancer. Wnt signals are transduced intracellularly by the Frizzled family of receptors. Moreover, proteoglycans and the co-receptors LRP5 and-6 participate in the transmission of Wnt signals, whereas a series of secreted antagonists can block Wnt signaling directly (i.e. Frzb and Sfrps) or indirectly (i.e. Dkks). Some of the biochemical interactions of the Wnts with their receptors and antagonists have recently been characterized, permitting further elucidation of how these proteins function in vivo. Expression pattern analyses in mouse embryos have shown that Wnt genes are active during most, if not all, developmental processes and gene inactivation has uncovered some of their key roles throughout mouse embryogenesis. Importantly, knockout and overexpression studies have proven the importance of Wnt signaling during mesoderm, neurectoderm and body axis formation. With their ability to differentiate into all adult cell types in vitro, mouse embryonic stem (ES) cells have been used to mimic the developing embryo. In this ES cell system, it has recently been shown that Wnt signals contribute to meso-derm induction and neural inhibition. Here we will provide an overview of the Wnt signaling pathway and its roles during mouse embryo-nic development, focusing on gastrulation. Functional studies in the mouse, including gene ablation and overexpression experiments, will be reviewed. Finally, we will discuss the latest reports on the application of ES cells to study the Wnt pathway during development.