Signal transduction in skin appendage pattern formation

During development, the integument forms to cover and protect the entire body. The specialized structures and functions of appendages result from serial interactions of the epithelium and mesenchyme. Morphogenesis of different appendages share similar molecular bases and cellular behaviors such as migration, proliferation, differentiation, and apoptosis; leading to the formation of skin appendages. In study we focus primarily on the signaling networks and cellular events during periodic pattern formation and the determination of individual appendage axis after initiation. The FGF signaling is required for the initiation of the skin appendage formation and has been found to function as an activator during skin appendage pattern formation. However, the downstream events and the regulation of cellular events during periodic pattern formation are still unclear. Screening by pharmaceutical drugs, MAPK/ERK pathway was found to be the major downstream effector for skin appendage pattern formation. This result was further confirmed by blocking fibroblast growth factor receptor (FGFR) by retroviral vector with soluble dominant negative FGFR and siRNA targeting Raf, which is upstream of ERK. All these data showed that MAPK signaling pathway is the major downstream pathway in response to FGF signaling. FGF/MAPK function plays as chemoattrantant to induce dermal condensation. Inhibiting FGF/MAPK signaling causes scattering of mesenchymal cells. The consequence of failure to complete dermal condensation results in the formation of stripe-shaped feather buds.;Following the consolidation of feather primodia, feather bud is further transformed from the radial symmetry to anterior-posterior (A-P) asymmetry growing axis. Down-regulation of both Delta1 and L-fringe altered feather orientation. After the axis is determined, the size of appendage is determined. Over-expression of Ras induces epidermis proliferation in feather primodia, and invagination during feather bud development. In the adult, Ras over-expression perturbs feather. Over-expression of c-myc increases the size of feather with normal appearing feather. These data suggest that Ras function is primarily acting on epithelium during development and regeneration. In summary, I showed the involvement of several signaling pathways in the arrangement, orientation, and shaping of skin appendages. These are important principles we need to know in the coming of tissue engineering of stem cells.