Paracrine Wnt ligands participate in cell-cell communication by activating several different signaling pathways including the WNT/B-catenin pathway which stabilizes cytoplasmic b-catenin allowing it to enter the nucleus and activate transcription in partnership with LEF/TCF transcription factors, and non-canonical pathways that control epithelial planar cell polarity, the actin cytoskeleton, cell movements, and cell adhesion. These pathways can interact with each other, and perform critical functions in skin and hair follicle development and disease. However, the mechanisms by which signaling is limited and controlled to provide proper patterning of hair follicle development, and the ligands, receptors and downstream components that provide specificity to Wnt functions in the skin are incompletely identified. Delineating the components of these pathways and dissecting their mechanisms of action will be critical for developing strategies for skin and hair follicle regeneration in cases of congenital absence or loss, and for the treatment of hair growth disorders and epidermal tumors. To determine the mechanisms by which WNT/b-catenin signaling is controlled and patterned in the skin, uncover novel functions of non-canonical Wnt signaling, and identify receptors mediating these pathways, we will: (1) Identify secreted inhibitors that limit WNT/B-catenin pathway activity and pattern hair follicle development in embryonic skin;(2) Determine whether the non-canonical Wnt pathway components Daam1 and Daam2 act downstream of Wnt5a and control proliferation and hair follicle stem cell maintenance by regulating the actin cytoskeleton;(3) Test the hypothesis that the closely related Wnt receptors Fzd1 and Fzd2 mediate both b-catenin-dependent and non-canonical Wnt signaling pathways in developing and hair follicles and epidermis.
Development and maintenance of the epidermis and hair follicles requires extensive communication between different cell types, and defective or dysregulated communication pathways can lead to hair loss disorders and skin cancers. Secreted Wnt proteins activate several different signaling pathways in recipient cells and play key roles in skin and hair development, hair growth, and tumorigenesis. The goal of this proposal is to delineate mechanisms that control Wnt activity, and to identify receptors and downstream components that provide specificity to Wnt functions in the skin and could provide novel therapeutic targets for hair loss diseases and skin cancers.
