The long-term objective of this laboratory is to understand the molecular basis of epithelial appendage morphogenesis. Epithelial appendages including hair, nail, feather, teeth, etc. are integral parts of the integument. Diseases and injuries involving these appendages can be detrimental to the survival of the animal. However, research on the development and regeneration of epithelial appendages has lacked. We hope this research will form the basis to promote novel approaches and ideas to manage pathological conditions involving epithelial appendages. We use the chicken feather as an experimental model. In the last funding period, we studied the roles of adhesion molecules and searched for their regulators. We found heterogenous molecular distribution in the epithelial placode develop from an initially homogeneous feather primordia. Molecules like Sonic hedgehog and FGF4 are radically symmetrically distributed, while others become anterior-posterior asymmetrically compartmentalized, with BMP2, 4 and Msx1, 2 in the anterior side, Serrate 1, Wnt7a, BrdU labeling in the posterior side, and Notch 1 forming a mid-stripe. Preliminary perturbation of the molecular balance arrested placode outgrowth in different ways. We hypothesize that the interactions between the anterior and posterior compartments are essential for the generation of a continuous growth zone required to drive the formation of the proximal-distal axis. This growth zone later becomes the feather collar (=hair matrix). Failure to form the growth zone leads to limited growth as seen in scale, but can be rescued to form feather buds by retinoic acid which may induce an ectopic compartment. This process is analogous to the formation of Drosophila appendages from epithelial imaginal discs and the limb bud apical ectodermal ridge, resulting from interactions between dorsal and ventral compartment signals. To test the hypothesis, we will use in situ, BrdU labeling and DiI labeling to establish molecular expression pattern and cell behavior. Differences among scales, feathers and feathery scales will be compared. For molecular candidates, we will focus on Notch and Wnt 7a pathways, and their interactions with other molecules. Retroviral gene transduction together with embryology techniques will be used to generate several experimental conditions including gene over-expression, dominant negative receptors, virus susceptible/resistant chimeric explants, and juxtaposition of anterior/posterior domains. Results and techniques developed here will advance our understanding in epithelial appendage morphogenesis and contribute to the development of gene therapy on hair matrix cells or dissociated keratinocytes for the regeneration of fully functional skin.
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