Mammals generate external coloration via dedicated pigment-producing cells but arrange pigment into patterns through mechanisms largely unknown. Here, using mice as models, we show that patterns ultimately emanate from dedicated pigment-receiving cells. These pigment recipients are epithelial cells that recruit melanocytes to their position in the skin and induce the transfer of melanin. We identify Foxn1 (a transcription factor) as an activator of this "pigment recipient phenotype" and Fgf2 (a growth factor and Foxn1 target) as a signal released by recipients. When Foxn1 - and thus dedicated recipients - are redistributed in the skin, new patterns of pigmentation develop, suggesting a mechanism for the evolution of coloration. We conclude that recipients provide a cutaneous template or blueprint that instructs melanocytes where to place pigment. As Foxn1 and Fgf2 also modulate epithelial growth and differentiation, the Foxn1 pathway should serve as a nexus coordinating cell division, differentiation, and pigmentation.

Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12 ؊/؊ mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12 ؊/؊ stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12 ؊/؊ skin. This was associated with a profound reduction in skin linoleic esters of long-chain -hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because -hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of longchain ceramide esters that are essential for the development of normal skin structure and function. Harlequin ichthyosis (HI)2 is the most severe of the congenital, autosomal ichthyoses with affected infants developing large, hard, plate-like scales over all of their epidermal surfaces. Abnormal temperature regulation, enhanced water loss, and bacterial super-infections develop as a consequence of defects in the barrier functions of the skin, making survival through the neonatal period difficult. In recent years, several groups have linked HI, as well as less severe forms of ichthyosis, to mutations in the gene encoding a member of the ABCA family of transporters, ABCA12 (1-7). The A class of ABC transporters consists of at least eleven transporters in humans and mice, several of which are known to play critical roles in human disease. ABCA1, the best studied of the proteins, is causally linked to Tangier disease and is associated with defective phospholipid and cholesterol transport from intracellular lipid stores to the major amphipathic helical apoprotein of high density lipoprotein, apolipoprotein A-1 (8 -11). ABCA3 mutations cause a form of neonatal respiratory failure that arises from a failure to transport pulmonary phospholipids comprising surfactant from their storage site in the lamellar bodies of alveolar type II cells to the alveolar space (12)(13)(14). This transport process, like the one involving ABCA1, appears to depend on the lipidation of an acceptor amphipathic helical protein, surfactant protein B (15, 16). ABCA4 causes Stargadt macular degeneration and visual loss that is associated with a defect in the transport of phosphatidylethanolamine-retinylidene adducts out of retinal pigment epithelial cells (17)(18)(19). The role of any acceptor proteins in this process is unknown. T...

p63, a p53 family member, is essential for the development of various stratified epithelia and is one of the earliest markers of many ectodermal structures, including the epidermis, oral mucosa, apical ectodermal ridge, and mammary gland. Genetic regulatory mechanisms controlling p63 spatial expression during development have not yet been defined. Using a genomic approach, we identified an evolutionarily conserved cis-regulatory element, located 160 kb downstream of the first p63 exon, which functions as a keratinocyte-specific enhancer and is sufficient to recapitulate expression of the endogenous gene during mouse embryogenesis. Dissection of the p63 enhancer activity revealed a positive autoregulatory loop in which the p63 proteins directly bind to and are essential regulators of the enhancer. Accordingly, transactivating p63 isoforms induce endogenous p63 expression in cells that do not normally express this gene, whereas dominant negative isoforms suppress p63 expression in keratinocytes. In addition the transcription factor AP-2 also binds to the enhancer and cooperates with p63 to induce its activity. These results demonstrate that a long-range autoregulatory loop is involved in the regulation of p63 expression during embryonic development and in adult cells.