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 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 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 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 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 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     

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.     

FGF-FGFR signaling in vertebrate organogenesis.

Fibroblast growth factor and FGF receptor (FGFR) system play significant roles in many biological events including pattern formation in many tissues during vertebrate embryogenesis at early stages. The functions of each of FGFs and their receptors have recently been revealed by a variety of approaches among species. We have recently generated FGF10-deficient mice by gene targeting. This KO mice had complete truncation of the fore-and hindlimbs and with no lung. Analyses of the embryos and marker gene expression showed that FGF10 triggers sequential events, which are essential for formations of limb and lung. Focusing on FGF10 function, the FGF-FGFR system is discussed.     

Wnt signaling in the niche

There is much interest in understanding the signals in the bone marrow niche that keep hematopoietic stem cells (HSCs) in a quiescent state. In the current issue of Cell Stem Cell, Fleming et al. (2008) report that blocking Wnt signaling in the niche increases the number of proliferating HSCs and reduces their ability to reconstitute the hematopoietic system of irradiated recipient mice. These findings show that Wnt/beta-catenin activity is crucial for the maintenance of HSC quiescence in the bone marrow niche.     

Wnt signaling involvement in beta-amyloid-dependent neurodegeneration

Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-beta peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients.