Wnt proteins are now recognized as one of the major families of developmentally important signaling molecules, with mutations in Wnt genes displaying remarkable phenotypes in the mouse, Caenorhabditis elegans, and Drosophila. Among functions provided by Wnt proteins are such intriguing processes as embryonic induction, the generation of cell polarity, and the specification of cell fate. Until recently, our knowledge of the molecular mechanism of Wnt signaling was very limited, but over the past year, several major gaps have been filled. These include the identification of cell-surface receptors and a novel mechanism of relaying the signal to the cell nucleus. In addition, several components of Wnt signaling are implicated in the genesis of human cancer. These insights have come from different corners of the animal kingdom and have converged on a common pathway. At this junction in this rapidly evolving field, we review our current understanding of Wnt function and signaling mechanisms, doing so in a comparative approach. We have put emphasis on the latest findings, highlighting novelty and underscoring questions that remain. For additional literature, we refer to several previous reviews (McMahon 1992; Nusse and Varmus 1992; Klingensmith and Nusse 1994; Miller and Moon 1996; Moon et al. 1997). We have limited the number of references, particularly in the tables. Fully referenced forms of these tables can be found on the Wnt homepage (http://wwwleland.stanford.edu/∼rnusse/wntwindow.html).

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Wnt signaling: a common theme in animal development

Analysis of Development Edited by Prof Benjamin H Willier, Prof Paul A Weiss and Prof Viktor Hamburger Pp xii + 735 (Philadelphia and London: W B Saunders Company, 1955) 105s

Mechanisms of Development

WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

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Can we safely target the WNT pathway

Dishevelled Activates JNK and Discriminates between JNK Pathways in Planar Polarity and wingless Signaling

https://www.oarsijournal.com/article/S1063-4584(99)90306-0/pdf

Cellular interactions and signaling in cartilage development.

The murine dishevelled 2 (Dvl2) gene is an ortholog of the Drosophila segment polarity gene Dishevelled, a member of the highly conserved Wingless/Wnt developmental pathway. Dvl2-deficient mice were produced to determine the role of Dvl2 in mammalian development. Mice containing null mutations in Dvl2 present with 50% lethality in both inbred 129S6 and in a hybrid 129S6-NIH Black Swiss background because of severe cardiovascular outflow tract defects, including double outlet right ventricle, transposition of the great arteries and persistent truncus arteriosis. The majority of the surviving Dvl2(-/-) mice were female, suggesting that penetrance was influenced by sex. Expression of Pitx2 and plexin A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural crest development during outflow tract formation. In addition, approximately 90% of Dvl2(-/-) mice have vertebral and rib malformations that affect the proximal as well as the distal parts of the ribs. These skeletal abnormalities were more pronounced in mice deficient for both Dvl1 and Dvl2. Somite differentiation markers used to analyze Dvl2(-/-) and Dvl1(-/-);Dvl2(-/-) mutant embryos revealed mildly aberrant expression of Uncx4.1, delta 1 and myogenin, suggesting defects in somite segmentation. Finally, 2-3% of Dvl2(-/-) embryos displayed thoracic spina bifida, while virtually all Dvl1/2 double mutant embryos displayed craniorachishisis, a completely open neural tube from the midbrain to the tail. Thus, Dvl2 is essential for normal cardiac morphogenesis, somite segmentation and neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in some phenotypes.

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Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure

http://web.stanford.edu/group/axelrodlab/papers/Klingensmith_etal.MOD96.pdf

Conservation of dishevelled structure and function between flies and mice : isolation and characterization of dvl2

The Drosophila dishevelled (dsh) segment polarity gene is required to establish cell fates specified by wingless/Wnt signal transduction during development. We have previously reported the cloning and characterization of a mouse homolog of dishevelled, Dvl1. Utilizing RT-PCR with degenerate primers, we isolated another member of the mouse Dishevelled (Dvl) gene family, Dvl3. The Dvl3 gene maps to mouse chromosome 16. The predicted amino acid sequence shares 64 and 62% identity to Dvl1 and Dvl2, respectively. The region of highest conservation between all three Dvl coding regions, at 97% identity, is noted at the PDZ domain (also termed the DHR domain or GLGF motif), a motif of 60 amino acids present in all dishevelled encoded proteins and first described in the Drosophila discs large (dlg) tumor suppressor gene. In adult mice, Dvl3 expression is widespread with highest levels exhibited in brain, ovary, and heart. In embryos, Dvl3 is expressed in every tissue between 7.5 and 9.5 days postcoitum, and by 10.5 days postcoitum highest expression was seen in the dorsal root ganglia, somites, limb buds, branchial arches, heart, gut and throughout the developing central nervous system.

Yasheng Yang

Papers

Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure

Conservation of dishevelled structure and function between flies and mice : isolation and characterization of dvl2

Isolation and characterization of mouse dishevelled-3.

Genomic organization of mouse Dishevelled genes.