The wide world of Wnts

Abstract

Researchers studying the Wnt pathway frequently like to joke that `Wnts do everything', and that this fact keeps us all in business. Over time, this claim has become less facetious, as the number of known roles for Wnt signaling has grown rapidly. Following on from the first identified functions of Wnts in embryonic tissue patterning and cell proliferation, these signals and their multiple downstream pathways have been implicated in everything from epithelial polarity to synapse formation. The authors of Wnt Signaling in Embryonic Development, edited by Sergei Sokol, have attempted to tackle this well characterized and highly important family of molecules and their complex functions. So much new research has been published on Wnt signaling in recent years that this collection of review articles is timely, giving readers an overview of recent findings as well as a more general perspective.FIG1The realization that a relatively small group of extracellular signals can regulate multiple aspects of development throughout the animal kingdom is both advantageous and daunting. On the plus side, it means that a limited set of tools and reagents can be used to perturb signaling in one's organism or tissue of choice, and to analyze the resulting phenotypic effects. The negative side is that understanding the roles of even one of these signals can be challenging; it seems that new functions and components are discovered every day. This can be contrasted with roles of Wnt signaling in cancer, where a few key events, such as proliferation, survival and anchorage-independent growth, receive most of the attention. Because of the vast number of organs and cellular events involved in development, one hope would be to identify common functions for Wnt signaling that can be extrapolated to hypothesis-based experiments in other developmental processes.This book is presumably aimed at biologists who want to know more about the roles of Wnt signaling in a particular developmental process, and to have a list of tools and phenotypic analyses available to answer a specific question. With this basic information, any researcher can perform gain- or loss-of-function studies in their favorite cell type, and also examine the expression of pathway components and targets. To this end, Dr Sokol has assembled a group of individual reviews from leaders in the field, each focused on a different aspect of Wnt signaling. These authors provide a level of expertise and insight into their respective topics that is difficult to achieve in other formats, and gives the reader confidence that they are receiving the most up-to-date information available.This book is akin to an encyclopedia without alphabetization. Most facts that a reader might want to know are in there somewhere, it's just a matter of finding themThe major weakness of such a compendium is, however, that although the individual chapters are comprehensive and useful, it becomes difficult to synthesize information between them. This is perhaps an unavoidable consequence of the structure of such a book, when each review is essentially independent in focus, although the preface partially helps to tie things together. Because the chapters are also quite divergent in scope, some material is unnecessarily repeated, whereas other findings are missed. A reader might have difficulty knowing where to look for particular information,as some chapters emphasize the signaling pathway itself, whereas others have an organism-centered approach and describe many known roles in a single animal, while the remainder deal specifically with Wnt function in individual tissues.Two chapters are organized around the best-understood output of Wnt signaling, transcriptional regulation via the `canonical' or β-catenin pathway. The first by David Parker, Timothy Blaukamp and Ken Cadigan focuses on the biochemical and genetic roles of nuclear components of this pathway throughout animal species, and provides a comprehensive overview of this ever-growing list of molecules. To understand the complexity of this system,one only need view the Wnt homepage schematic generated by Roel Nusse(http://www.stanford.edu/~rnusse/pathways/cell2.html)and view the jumble of factors that occupies the entire nucleus. While covering a lot of ground, this review provides an important reference for anyone interested in Wnt-mediated transcription. By contrast, a chapter by Henrick Korswagen centers specifically on roles of the POP-1 transcription factor in a single organism, C. elegans. It provides a more in-depth analysis of a relatively small number of genes and their mutant phenotypes,with useful descriptions of the cellular processes affected. Together, these two chapters provide complimentary overviews of canonical Wnt signaling. Reading both leaves one with a detailed understanding of the mechanism through which Wnts regulate target gene transcription, and examples of the functional outputs of this pathway in a relatively simple model organism.Another chapter by Jianbow Wang, Leah Etheridge and Anthony Wynshaw-Boris,also covers roles for Wnt signaling in an entire (and much more complex)organism, the mouse. This is obviously an enormously broad topic, including multiple tissue types and different signaling outputs. Considering this, the authors have done a heroic job in summarizing a large volume of literature and provide a comprehensive background for readers interested in the range of Wnt activities in a single animal. The work described in this chapter helps illustrate how gene redundancy and pleiotropic effects have frustrated the ability of researchers to study Wnt function using genetic approaches. However, given the space available, it might have been more beneficial to have focused on either a single output or on fewer tissue types, but in greater depth. Some of the topics discussed here are covered in other chapters, and there is little room for the interpretation of phenotypes, which would help the non-specialist. The chapter ends up being very fact-dense, but is still useful as a general reference for the field.Two chapters focus on cellular functions of Wnt signaling, each with examples from different tissues and organisms. Gretchen Dollar and Sergei Sokol describe how Wnts control cellular polarity, including such well-studied events as apical-basal polarization, planar cell polarity, cell movement and asymmetric division. Each topic is introduced with sufficient background information, followed by genetic and biochemical evidence of Wnt pathway functions in the process. The common themes aid a reader in drawing parallels with their favorite system, and allow predictions for how Wnts might act in unstudied cell types. Almut Köhler, Alexandra Schambony and Doris Wedlich focus specifically on cell migration, using examples from mouse gastrulation,the nervous system, and formation of eye and heart fields. Similarities appear between single-cell and tissue-level migratory regulation, and classical embryological models, such as Xenopus gastrulation, are juxtaposed with newer topics, providing a comprehensive overview. Although it is not surprising that non-canonical Wnt signaling can affect cell migration in a variety of systems, this chapter also leaves the reader with the important idea that canonical signaling can regulate migration at the level of gene expression.Finally, two chapters discuss Wnt signaling functions in specific tissue types. Elizabeth Heeg-Truesdell and Carole LaBonne review multiple stages of neural crest development, providing evidence for regulation by Wnts at each step from crest induction to cellular differentiation. This chapter creates perhaps the clearest overview of how a single class of extracellular signals,through multiple downstream pathways, are used reiteratively throughout the development of one cell type. This is a fundamental concept in developmental biology, as is the idea that Wnts are likely to act in concert with other signals at all these steps. Néstor Masckauchán and Jan Kitajewski focus on Wnt pathways in angiogenesis, which is a relatively new direction of research that has uncovered known and novel members of the signaling cascade using genetic approaches. Most of the initial work has centered on diseases of the retinal vasculature, which have provided a good model for ligand and receptor activity in the growth and regression of vessels. These findings have led to the search for additional functions for Wnt signaling in angiogenesis, with obvious clinical implications. Together,these chapters illustrate the forward movement in the field towards translational research using Wnt pathway modulation to treat developmental disorders and disease.With all the data accumulated from hundreds of studies, one purpose of these chapters is to help separate the wheat from the chaff. A good chapter should not only summarize the data, but also act as a filter through the expertise of the author to help interpret the current state of the field. Is a finding significant, or is it a one-off observation? How do we interpret studies with directly contradictory conclusions? Some of the chapters are more successful at addressing these questions, offering interpretations of discrepancies in the literature and suggesting general themes. In other chapters, every finding is presented with equal weight, leaving it up to the reader to judge their importance. However, it is nice to see more-recent research directions represented in this book, such as angiogenesis and cell polarity, even if the significance of some of these studies is less clear at this point.Overall, this book is akin to an encyclopedia without alphabetization. Most facts that a reader might want to know are in there somewhere, it's just a matter of finding them (although the index is helpful). Because of this, one might be better served by reading through the entire volume, rather than searching for specific information in individual chapters. Editors of review compilations are limited by their ability to recruit authors with expertise,and Dr Sokol has brought together a first-rate group, possibly at the expense of a more-standardized selection of topics. The perfect book would have both.