Wnt Signaling in Skin Development, Homeostasis, and Disease

Abstract

The skin and its appendages constitute the largest organ of the body. Its stratified epithelia offer protection from environmental stresses such as dehydration, irradiation, mechanical trauma, and pathogenic infection, whereas its appendages, like hair and sebaceous glands, help regulate body temperature as well as influence animal interaction and social behavior through camouflage and sexual signaling. To respond to and function effectively in a dynamic external environment, the skin and its appendages possess a remarkable ability to regenerate in a carefully controlled fashion. When this finely tuned homeostatic process is disrupted, skin diseases such as cancers may result. At present, the molecular signals that orchestrate cell proliferation, differentiation, and patterning in the skin remain incompletely understood. It is increasingly apparent that many morphogenetic pathways with key roles in development are also important in regulating skin biology. Of these, Wnt signaling has emerged as the dominant pathway controlling the patterning of skin and influencing the decisions of embryonic and adult stem cells to adopt the various cell lineages of the skin and its appendages, as well as subsequently controlling the function of differentiated skin cells. Here we will review established concepts and present recent advances in our understanding of the diverse roles that Wnt signaling plays in skin development, homeostasis, and disease. (FIG. 1) WNT IN THE DEVELOPMENT OF SKIN AND ITS APPENDAGES

Wnt signaling induces epithelial differentiation during cutaneous wound healing

“…There is increasing evidence that Wnt proteins are necessary for normal skin development. 8,9,10 Recent data demonstrate that the epidermis of wounded adult mice can regenerate new hair follicles during healing and that the origins of cells that develop new hair follicles are Wntresponsive interfollicular stem cells, not stem cells from the existing hair follicle bulb.…”

HOXC8 initiates an ectopic mammary program by regulating Fgf10 and Tbx3 expression, and Wnt/β-catenin signaling

“…Wnt/β-catenin signaling is abnormally upregulated in mammary placode epithelium of W6cre/CAGC8 embryos As Wnt signaling is essential for the initiation and subsequent development of all ectodermal organs (Boras-Granic and Hamel, 2013; Chu et al, 2004;Lim and Nusse, 2013), we performed a detailed timeline of TOPgal reporter expression at different embryonic stages to study changes in Wnt signaling that accompany Hoxc8 dysregulation. W6cre/CAGC8 embryos survive until birth, enabling us to perform TOPgal analysis during mammary ductal elongation and branching.…”

Identification of Key Residues and Regions Important for Porcupine-mediated Wnt Acylation

“…Wnt proteins activate signaling cascades that result in the transcription of genes involved in proliferation, differentiation, and migration. Aberrant activation of the Wnt signaling pathway has been linked to a variety of human cancers, including melanoma, breast, colon, and head and neck (9,13,14). Because of its importance in diseases, there is significant interest in understanding the biochemistry of Wnt processing and secretion.…”