Dynamic Plasticity of Axons within a Cutaneous Milieu

Abstract

The skin is a repository of sensory axons immersed within the turnover of epidermal, follicular, and dermal cellular constituents. We show that epidermal and perifollicular axons within intact hairy skin of mice possess a remarkable dynamic plasticity linked to their microenvironment. For example, the majority of epidermal axons express the growth protein GAP43. Unexpectedly, we induced new cutaneous axogenesis by simple and noninvasive hair clipping, a response linked to a series of changes in their cutaneous neighbors. In thy-1 YFP transgenic mice with fluorescent axons, superficial epidermal and perifollicular cells newly acquired YFP, indicating diffuse activation by clipping despite the absence of skin injury. At 48 h after clipping, this activation was accompanied by a rise in the number of epidermal cells, transient rises in mRNA of Sox2, a marker of follicular stem cells, and a rise in mRNA of glial fibrillary acidic protein, a marker of glial cells. Axons responded with rises in their numbers in the epidermis and around dermal hair follicles. Linking these responses were early, large, and selective rises in hepatic growth factor (HGF) mRNA, with its protein identified in epidermal cells, perifollicular cells, and sensory axons. Moreover, these elements also expressed the HGF receptor c-Met, especially in small caliber sensory neurons. Finally, we identified concurrent rises in Rac1 activation, a downstream target of ligated c-Met. Together, these results confirm critical linkages between sensory axons and their cutaneous milieu. We believe that the plasticity is provoked by follicular-originating cutaneous activation with HGF and Rac1 signaling, allowing cross talk and axonal remodeling.