An Ideal Society? Neighbors of Diverse Origins Interact to Create and Maintain Complex Mini-Organs in the Skin

T he largest organ in the body, the skin provides protection against environmental insults and dehydration, and is an important gateway for sensory input. In addition to forming an environmental barrier, the skin has evolved to produce an amazing variety of appendages, including scales, feathers, hair follicles, sweat glands, and mammary glands (Figure 1). These organs arise from embryonic skin progenitor cells and endow wide-ranging properties, including regulation of body temperature, and the ability to fl y, nurse young, and attract mates. As the body's primary frontier, the skin is both vulnerable to disease, such as melanoma, and a source of therapeutic promise, harboring accessible stem cells (SCs) that can regenerate skin and potentially other organs. Mammalian skin contains three major cell types: epithelial cells that form a stratifi ed epidermis containing specialized intermediate fi lament proteins called keratins; mesenchymal cells that form the underlying dermis and, together with epithelial cells, contribute to hair follicles and other appendages; and melanocytes that provide the skin and hair follicles with pigmentation. In addition, the skin is highly innervated, and contains populations of specialized cells including dentritic Langerhans cells (a type of antigen presenting cell), Merkel mechanoreceptor cells (which form complexes with sensory axons), and mast cells (which produce histamine). These different cell types have diverse origins, and undergo extensive interactions, migration, proliferation, and differentiation during embryonic development. Morphogenesis is controlled by a relatively small number of key intercellular signaling pathways that occur sequentially and in specifi c combinatorial fashions. Activation of these pathways is directed by secreted ligands, including members of the WNT, fi broblast growth factor, tumor necrosis factor, and Hedgehog families, and bone morphogenetic protein (BMP) and other transforming growth factor superfamily members, which act over relatively short distances and bind to specifi c receptor proteins on neighboring cells to regulate cell shape, size, adhesion, polarity, movements, proliferation, and transcriptional activity. The molecular events underlying skin development in mammals have been studied using a variety of systems and techniques. These include analysis of human genetic syndromes and spontaneously occurring and induced mouse mutants, production of transgenic and gene-targeted mouse models, in vitro culture of rodent and human skin cells, and grafting of human or rodent skin to immune-defi cient mice. The epidermis originates from the outer layer of the embryo, the surface ectoderm. BMPs activate the epidermal differentiation program and induce the expression of keratin proteins via several known transcription …