Cheng-Ming Chuong, Department of Pathology, Univ. Southern California, Los Angeles, CA 90033, USA.

Skin appendages are derivatives of epidermal epithelia that elaborate to form specialized structures and functions. Epithelia can protrude to form hairs, feathers, nails or invaginate to form glands. During development, each type of appendage goes through induction, morphogenesis, differentiation, and cycling / regenerative stages, and is variation of top of a common theme. Here we use the feather as a model to analyze the molecular circuitry and cellular events in skin appendage development. In induction stage, cells in the skin appendage field were initially equivalent. Driven by cell adhesion force (e.g., NCAM) and regulated by secreted signaling molecules involving a reaction-diffusion mechanism (e.g., FGF, BMP, noggin, follistatin), cells self-organize to reach a competitive equilibrium state of periodically arranged feather primordia. In morphogenesis stage, primordia first acquire antero-posterior axises from the epithelia, with wnt 7a located in the posterior epithelia and delta-1 restricted to the posterior mesenchyme. Interactions between anterior and posterior bud domains lead to the generation of the bud growth zone (BuGZ), enriched with sonic hedgehog, that sustains the growth in proximal - distal direction and results in the elongation of skin appendages. During morphogenesis stage, the phenotypes are not irreversibly determined and can be converted by reagents such as retinoic acid. We now show that over-expression of constitutively active $ catenin in scale epidermis can convert domains of the avian scale into feathers. Finally, in differentiation stage, distinct cyto-differentiation of keratinocytes endows different properties to each uniquely constructed skin appendage. We propose that during evolution, the activation of basic gene circuitry in epidermal precursor cells leads to the formation of prototypes of skin appendages. These form malleable media that endows vertebrates to form diverse integuments and appendages to interact and adapt to different niches in the constantly changing Nature. Knowing how these molecular and cellular events work during skin appendage development will help us in diseases and tissue engineering involving skin and its skin appendages.