L-03   MOLECULAR MECHANISMS CONTROLLING THE MELANOCYTE FATE DURING HAIR FOLLICLE DEVELOPMENT AND CYCLING

NV Botchkareva. The Gillette Company, Needham, MA, USA.

During hair follicle morphogenesis, melanocyte precursors migrate into developing hair follicles and give rise to differentiated melanocytes that actively produce and transport pigment into keratinocytes that form the hair shaft. Proliferating melanocyte precursors (TRP2/Ki67+cells) are seen in the hair follicles at stages 1-2 of morphogenesis, as follicular invagination begins. In stage 3-4 hair follicles, the majority of intrafollicular melanocytes remain TRP2+ and Ki67+, while some located adjacent to the forming dermal papilla begin to express TRP1, an early marker of differentiation. Melanin granules appear in stage 5 hair follicles coincident with tyrosinase expression in non-proliferating TRP2+/TRP1+ melanocytes. Stage 6-8 hair follicles, those actively producing hair, show non-proliferating TRP2+ melanocytes in the bulge area, TRP2+/TRP1+ melanocytes in the outer root sheath, and TRP2+/TRP1+/tyrosinase+ melanocytes above the dermal papilla. Stem cell factor (SCF) and its receptor c-kit are important for melanocyte survival during development, and mutations in these genes result in unpigmented hairs. During the hair cycle, proliferating, differentiating, and melanin-producing melanocytes express c-kit, while presumptive melanocyte stem cells do not. SCF overexpression in HF epithelium significantly increases the number and proliferative activity of melanocytes. During postnatal hair cycle, administration of anti-c-kit antibody dose-dependently decreases hair pigmentation and leads to partially depigmented (gray) or fully depigmented (white) hairs, associated with significant decreases in melanocyte proliferation and differentiation, as determined by immunostaining and confocal microscopy. However, in the next hair cycle the previously treated animals grow fully pigmented hairs with the normal number and distribution of melanocytes. This suggests that melanocyte stem cells are not dependent on SCF/c-kit and when appropriately stimulated can generate melanogenically-active melanocytes. Therefore, the blockade of c-kit signaling offers a fully reversible model for hair depigmentation, which might be used for the studies of hair pigmentation disorders.