WNT Signals in Skin and Hair Development and Growth

描述(申请人提供)：旁分泌Wnt配体通过激活几个不同的信号通路参与细胞间的交流，包括Wnt/B-catenin通路，它稳定细胞质中的b-catenin，使其能够进入细胞核并与Lef/Tcf转录因子一起激活转录，以及控制上皮平面细胞极性、肌动蛋白细胞骨架、细胞运动和细胞黏附的非规范通路。 这些途径可以相互作用，并在皮肤和毛囊发育和疾病中发挥关键作用。然而，限制和控制信号以提供毛囊发育的适当模式的机制，以及为皮肤中的Wnt功能提供特异性的配体、受体和下游成分还没有完全确定。描述这些通路的组成部分并剖析它们的作用机制，对于制定先天性缺失或缺失情况下皮肤和毛囊再生的策略，以及治疗毛发生长障碍和表皮肿瘤至关重要。为了确定WNT/b-catenin信号在皮肤中的调控和模式形成的机制，揭示非规范Wnt信号的新功能，并确定介导这些途径的受体，我们将：(1)鉴定限制Wnt/B-catenin途径活性和胚胎皮肤毛囊发育的分泌型抑制物；(2)确定非典型Wnt途径组件Daam1和Daam2是否作用于Wnt5a下游，通过调节肌动蛋白细胞骨架来控制毛囊干细胞的增殖和维持；(3)验证密切相关的Wnt受体Fzd1和Fzd2在发育、毛囊和表皮中既介导b-连环素依赖性信号通路又介导非典型性Wnt信号通路的假设。

DESCRIPTION (provided by applicant): 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.