Apical-basal polarity, Wnt signaling and vertebrate organogenesis

Wnt proteins elicit several distinct signal transduction cascades and regulate multiple cellular processes that have proven essential for embryonic development in all metazoans investigated. During embryonic development, epithelial cells become polarized along two axes: apical/basal and within the plane of the tissue. Growing evidence suggests that polarization along each axis is essential for normal embryonic development and that this polarization is regulated in part by the different branches of the Wnt pathway. Here, we review the role of A/B cell polarity in vertebrate organogenesis with a focus on the involvement of canonical Wnt signaling in this process.     

Planar cell polarity and vertebrate organogenesis

In addition to being polarized along their apical/basal axis, cells composing most (if not all) organs are also polarized in a plane vertical to the A/B axis. Recent studies indicate that this so-called planar cell polarity (PCP) plays an essential role in the formation of multiple organ systems regulating directed cell migrations, polarized cell division and proper differentiation. In this review we will discuss the molecular mechanisms regulating PCP, including the hypothesized roles for Wnt ligands in this process, and its roles in vertebrate organogenesis.     

Planar cell polarity regulators in asymmetric organogenesis during development and disease

The phenomenon of planar cell polarity is critically required for a myriad of morphogenetic processes in metazoan and is accurately controlled by several conserved modules. Six “core” proteins, including Frizzled, Flamingo (Celsr), Van Gogh (Vangl), Dishevelled, Prickle, and Diego (Ankrd6), are major components of the Wnt/planar cell polarity pathway. The Fat/Dchs protocadherins and the Scrib polarity complex also function to instruct cellular polarization. In vertebrates, all these pathways are essential for tissue and organ morphogenesis, such as neural tube closure, left–right symmetry breaking, heart and gut morphogenesis, lung and kidney branching, stereociliary bundle orientation, and proximal–distal limb elongation. Mutations in planar polarity genes are closely linked to various congenital diseases. Striking advances have been made in deciphering their contribution to the establishment of spatially oriented pattern in developing organs and the maintenance of tissue homeostasis. The challenge remains to clarify the complex interplay of different polarity pathways in organogenesis and the link of cell polarity to cell fate specification. Interdisciplinary approaches are also important to understand the roles of mechanical forces in coupling cellular polarization and differentiation. This review outlines current advances on planar polarity regulators in asymmetric organ formation, with the aim to identify questions that deserve further investigation.     

Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity

Scratch-induced disruption of cultured monolayers induces polarity in front row cells that can be visualized by spatially localized polymerization of actin at the front of the cell and reorientation of the centrosome/Golgi to face the leading edge. We previously reported that centrosomal reorientation and microtubule polarization depend on a Cdc42-regulated signal transduction pathway involving activation of the Par6/aPKC complex followed by inhibition of GSK-3beta and accumulation of the adenomatous polyposis coli (APC) protein at the plus ends of leading-edge microtubules. Using monolayers of primary rodent embryo fibroblasts, we show here that dishevelled (Dvl) and axin, two major components of the Wnt signaling pathway are required for centrosome reorientation and that Wnt5a is required for activation of this pathway. We conclude that disruption of cell-cell contacts leads to the activation of a noncanonical Wnt/dishevelled signal transduction pathway that cooperates with Cdc42/Par6/aPKC to promote polarized reorganization of the microtubule cytoskeleton.     

Wnt/planar cell polarity signaling

The limb is one of the premier models for studying how a simple embryonic anlage develops into complex three-dimensional form. One of the key issues in the limb field has been to determine how the limb becomes patterned along its proximal (shoulder/hip) to distal (digits) axis. For decades it has been known that the apical ectodermal ridge (AER) plays a crucial role in distal outgrowth and patterning of the vertebrate embryonic limb. Most studies have explored the relationship between the AER and the progressive assignment of cell fates to mesenchyme along the proximal to distal (PD) axis. Comparatively few, however, have examined the additional role of the AER to regulate distal outgrowth of the limb and how this growth may also influence pattern along the PD axis. Here, I will review key studies that explore the role of growth in limb development. In particular, I will focus on a recent flurry of papers that examine the role of the Wnt/planar cell polarity (PCP) pathway in regulating directed growth of the limb mesenchyme. Finally, I will discuss a potential mechanism that relates the AER to the Wnt/PCP pathway and how directed growth can play a role in shaping the limb along the PD axis.     

Crosstalk of cell polarity signaling pathways

Cell polarity, the asymmetric organization of cellular components along one or multiple axes, is present in most cells. From budding yeast cell polarization induced by pheromone signaling, oocyte polarization at fertilization to polarized epithelia and neuronal cells in multicellular organisms, similar mechanisms are used to determine cell polarity. Crucial role in this process is played by signaling lipid molecules, small Rho family GTPases and Par proteins. All these signaling circuits finally govern the cytoskeleton, which is responsible for oriented cell migration, cell shape changes, and polarized membrane and organelle trafficking. Thus, typically in the process of cell polarization, most cellular constituents become polarized, including plasma membrane lipid composition, ion concentrations, membrane receptors, and proteins in general, mRNA, vesicle trafficking, or intracellular organelles. This review gives a brief overview how these systems talk to each other both during initial symmetry breaking and within the signaling feedback loop mechanisms used to preserve the polarized state.     

Wnt signaling in eye organogenesis

The vertebrate eye consists of multiple tissues with distinct embryonic origins. To ensure formation of the eye as a functional organ, development of ocular tissues must be precisely coordinated. Besides intrinsic regulators, several extracellular pathways have been shown to participate in controlling critical steps during eye development. Many components of Wnt/Frizzled signaling pathways are expressed in developing ocular tissues, and substantial progress has been made in the past few years in understanding their function during vertebrate eye development. Here, I summarize recent work using functional experiments to elucidate the roles of Wnt/Frizzled pathways during development of ocular tissues in different vertebrates.Key words: eye, retina, ciliary body, lens, vasculature, Wnt, frizzled, mouse, frog, chick, zebrafish     

Wnt signaling in breast organogenesis

Wnt signals play a critical role in regulating the normal development of the mammary gland and dysregulation of Wnt signaling causes breast cancer. This pathway is involved in the earliest development of the mammary gland in embryos and its role extends through the functional differentiation of the gland during pregnancy. In this review, we summarize the molecular mechanisms through which Wnts regulate mammary gland development in the mouse.Key words: Wnt, mammary gland, embryo, postnatal, cancer, stem cell     

Wnt signaling in breast organogenesis

Wnt signals play a critical role in regulating the normal development of the mammary gland and dysregulation of Wnt signaling causes breast cancer. This pathway is involved in the earliest development of the mammary gland in embryos and its role extends through the functional differentiation of the gland during pregnancy. In this review, we summarize the molecular mechanisms through which Wnts regulate mammary gland development in the mouse.     

Wnt signaling in skin organogenesis

While serving as the interface between an organism and its environment, the skin also can elaborate a wide range of skin appendages to service specific purposes in a region-specific fashion. As in other organs, Wnt signaling plays a key role in regulating the proliferation, differentiation and motility of skin cells during their morphogenesis. Here I will review some of the recent work that has been done on skin organogenesis. I will cover dermis formation, the development of skin appendages, cycling of appendages in the adult, stem cell regulation, patterning, orientation, regional specificity and modulation by sex hormone nuclear receptors. I will also cover their roles in wound healing, hair regeneration and skin related diseases. It appears that Wnt signaling plays essential but distinct roles in different hierarchical levels of morphogenesis and organogenesis. Many of these areas have not yet been fully explored but are certainly promising areas of future research.Key words: morphogenesis, hair, feathers, tracts, epithelium-mesenchyme interactions, Wnt signaling pathwayThe integument forms the interface between an organism and its environment.^1,2 As such it protects against dehydration, infection, temperature extremes, etc while providing a means for display, camouflage and other functions.³ The skin can elaborate remarkable structural diversity producing specialized functions in a region-specific fashion to provide organisms with a selective advantage. For example, the development of feathers led to the acquisition of flight in birds and the formation of mammary glands enabled mammals to nurse their young.⁴ The advantage of these evolutionary developments can be seen by the number of birds and mammals present today.Skin appendages, such as skin, hairs, feathers, scales, glands and teeth grow from the epithelium as a result of epithelial-mesenchymal interactions,⁵ largely in response to common molecular signals with slight variations in their placement and timing during tissue morphogenesis.⁶ Theoretically, stem cells are totipotent and progressively can be guided toward their specific fates by exposure to specific regulatory signals. The juxtaposition of molecular signals or lack thereof may have a tremendous impact on cell fate decisions. Hence, the difference between skin appendages is due to the topological arrangement of the epithelia during developmental processes. These are presumably regulated by adhesion molecules whose expression is controlled by signaling molecules as well as by physical constraints.Hairs and feathers are attractive model systems for experimental research because of their ability for seasonal or periodic renewal. Obviously not all hairs or feathers are replaced at one time or birds would lose all of their feathers at once and fall from the sky in mid-flight; rather hairs and feathers are replaced over a period of time in a wave-like pattern.⁷ Yet this cycling behavior enables thousands of entirely new organs to be regenerated again and again throughout these animal''s lives. Hairs and feathers demonstrate an incredible diversity of forms arising in different locations over the body surface. For instance, hairs on the scalp, face and body differ in size, coarseness, color, etc. This regional specificity indicates that in each cycle skin stem cells are directed to form distinct structures through a series of molecular and cellular interactions.     

Wnt signaling in skin organogenesis

While serving as the interface between an organism and its environment, the skin also can elaborate a wide range of skin appendages to service specific purposes in a region-specific fashion. As in other organs, Wnt signaling plays a key role in regulating the proliferation, differentiation and motility of skin cells during their morphogenesis. Here I will review some of the recent work that has been done on skin organogenesis. I will cover dermis formation, the development of skin appendages, cycling of appendages in the adult, stem cell regulation, patterning, orientation, regional specificity, and modulation by sex hormone nuclear receptors. I will also cover their roles in wound healing, hair regeneration and skin related diseases. It appears that Wnt signaling plays essential but distinct roles in different hierarchical levels of morphogenesis and organogenesis. Many of these areas have not yet been fully explored but are certainly promising areas of future research.     

Wnt signaling in limb organogenesis

Secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development of a wide range of taxa from Hydra to humans. The most extensively studied Wnt signaling pathway is the canonical Wnt pathway, which controls gene expression by stabilizing β-catenin, and regulates a multitude of developmental processes. More recently, noncanonical Wnt pathways, which are β-catenin-independent, have been found to be important developmental regulators. Understanding the mechanisms of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. Limb development is a paradigm to study the principles of Wnt signaling in various developmental contexts. In the developing vertebrate limb, Wnt signaling has been shown to have important functions during limb bud initiation, limb outgrowth, early limb patterning, and later limb morphogenesis events. This review provides a brief overview on the diversity of Wnt-dependent signaling events during embryonic development of the vertebrate limb.     

Wnt signaling in limb organogenesis

Secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development of a wide range of taxa from Hydra to humans. The most extensively studied Wnt signaling pathway is the canonical Wnt pathway, which controls gene expression by stabilizing β-catenin, and regulates a multitude of developmental processes. More recently, noncanonical Wnt pathways, which are β-catenin-independent, have been found to be important developmental regulators. Understanding the mechanisms of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. Limb development is a paradigm to study the principles of Wnt signaling in various developmental contexts. In the developing vertebrate limb, Wnt signaling has been shown to have important functions during limb bud initiation, limb outgrowth, early limb patterning, and later limb morphogenesis events. This review provides a brief overview on the diversity of Wnt-dependent signaling events during embryonic development of the vertebrate limb.Key words: Wnts, limb initiation, outgrowth, patterning, morphogenesis     

Wnt signaling in lung organogenesis

Reporter transgene, knockout, and misexpression studies support the notion that Wnt/β-catenin signaling regulates aspects of branching morphogenesis, regional specialization of the epithelium and mesenchyme, and establishment of progenitor cell pools. As demonstrated for other foregut endoderm-derived organs, β-catenin and the Wnt/β-catenin signaling pathway contribute to control of cellular proliferation, differentiation and migration. However, the contribution of Wnt/β-catenin signaling to these processes is shaped by other signals impinging on target tissues. In this review, we will concentrate on roles for Wnt/β-catenin in respiratory system development, including segregation of the conducting airway and alveolar compartments, specialization of the mesencyme, and establishment of tracheal asymmetries and tracheal glands.     

Wnt signaling in lung organogenesis

Reporter transgene, knockout, and misexpression studies support the notion that Wnt/β-catenin signaling regulates aspects of branching morphogenesis, regional specialization of the epithelium and mesenchyme, and establishment of progenitor cell pools. As demonstrated for other foregut endoderm-derived organs, β-catenin and the Wnt/β-catenin signaling pathway contribute to control of cellular proliferation, differentiation and migration. However, the contribution of Wnt/β-catenin signaling to these processes is shaped by other signals impinging on target tissues. In this review, we will concentrate on roles for Wnt/β-catenin in respiratory system development, including segregation of the conducting airway and alveolar compartments, specialization of the mesenchyme, and establishment of tracheal asymmetries and tracheal glands.Key words: morphogenesis, respiratory, airway, alveolar, mesenchyme, endoderm